Sustained-release product comprising a combination of a non-opioid amine and a non-steroidal anti-inflammatory drug

ABSTRACT

Sustained-release oral pharmaceutical compositions and methods of use, wherein the compositions are in a single dosage form and include an amine-containing compound (including salts thereof), a salt of a non-steroidal anti-inflammatory drug (NSAID), and a hydrophilic matrix.

CONTINUING APPLICATION DATA

This application is a U.S. National Stage Application of InternationalApplication No. PCT/US2009/069912, filed on Dec. 31, 2009, published inthe English language on Mar. 24, 2011 as International Publication No.WO 2011/034554 A1, which claims the benefit of U.S. ProvisionalApplication Ser. No. 61/243,391, filed Sep. 17, 2009. Attention is alsodirected to PCT Patent Application No. PCT/US2009/069902, filed Dec. 31,2009, titled Opioid-Containing Oral Pharmaceutical Compositions andMethods, which claims the benefit of U.S. Provisional Application Ser.No. 61/141,765, filed Dec. 31, 2008. All of the above are incorporatedby reference herein.

BACKGROUND

For many pharmacologically active compounds, immediate-releaseformulations are characterized by a short duration of action, typicallynecessitating frequent administrations in order to maintain therapeuticlevels of the compounds in patients. Thus, there is a need for new oralpharmaceutical compositions that provide sustained release, and ideallyzero-order release kinetics, and less frequent dosing.

SUMMARY

The present invention provides sustained-release oral pharmaceuticalcompositions and methods of use.

In one embodiment, the present invention provides a sustained-releaseoral pharmaceutical composition comprising within a single dosage form:a hydrophilic matrix; a therapeutically effective amount of a non-opioidamine-containing compound (including salts thereof) (wherein the aminegroup can be a primary, secondary, or tertiary amine, or combinationthereof); and a salt of a non-steroidal anti-inflammatory drug (NSAID);wherein the amine-containing compound and the salt of an NSAID arewithin the hydrophilic matrix; wherein the composition exhibits arelease profile of the amine-containing compound comprising asubstantial portion that is representative of zero-order releasekinetics (with respect to the amine-containing compound) under in vitroconditions.

In another embodiment, the present invention provides asustained-release oral pharmaceutical composition comprising within asingle dosage form: a hydrophilic matrix; a therapeutically effectiveamount of a non-opioid amine-containing compound (including saltsthereof) (wherein the amine group can be a primary, secondary, ortertiary amine, or combination thereof); a salt of a non-steroidalanti-inflammatory drug (NSAID); and a pharmaceutically acceptableanionic surfactant; wherein the amine-containing compound, the salt ofan NSAID, and the anionic surfactant are within the hydrophilic matrix.Preferred compositions exhibit a release profile of the amine-containingcompound comprising a substantial portion that is representative ofzero-order release kinetics under in vitro conditions.

The amine-containing compounds of the present invention include one ormore amine groups. In certain preferred embodiments, theamine-containing compound comprises a tertiary amine. In certainembodiments, the amine-containing compound comprises a ring nitrogenthat is a tertiary amine. In other preferred embodiments, theamine-containing compound comprises a tertiary amine or a secondaryamine, or a combination thereof. Typically in the practice of thepresent invention, such amine-containing compounds are non-opioidcompounds.

In a preferred embodiment, the present invention provides asustained-release oral pharmaceutical composition comprising within asingle dosage form: a hydrophilic matrix; a therapeutically effectiveamount of an amine-containing compound selected from the groupconsisting of dextromethorphan, cyclobenzaprine, benztropine (alsosometimes referred to as benzatropine), salts thereof, and combinationsthereof; and a salt of a non-steroidal anti-inflammatory drug (NSAID)selected from the group consisting of a salt of naproxen, diclofenac,ibuprofen, and combinations thereof; wherein the amine-containingcompound and the salt of an NSAID are within the hydrophilic matrix;wherein the composition has a release profile of the amine-containingcompound comprising a substantial portion that is representative ofzero-order release kinetics under in vitro conditions.

In another preferred embodiment, the present invention provides asustained-release oral pharmaceutical composition comprising within asingle dosage form: a hydrophilic matrix; a therapeutically effectiveamount of an amine-containing compound selected from the groupconsisting of dextromethorphan, cyclobenzaprine, benztropine, saltsthereof, and combinations thereof; a salt of a non-steroidalanti-inflammatory drug (NSAID) selected from the group consisting of asalt of naproxen, diclofenac, ibuprofen, and combinations thereof; and apharmaceutically acceptable anionic surfactant selected from the groupconsisting of sodium lauryl sulfate, docusate sodium, docusate calcium,and combinations thereof; wherein the amine-containing compound, thesalt of an NSAID, and the anionic surfactant are within the hydrophilicmatrix. Preferred such compositions have a release profile of theamine-containing compound comprising a substantial portion that isrepresentative of zero-order release kinetics under in vitro conditions.

In a preferred embodiment, the present invention provides asustained-release oral pharmaceutical composition comprising within asingle dosage form: a hydrophilic matrix comprising a hydroxypropylmethylcellulose; a therapeutically effective amount of anamine-containing compound selected from the group consisting ofdextromethorphan, a salt thereof, and combinations thereof; and a saltof a non-steroidal anti-inflammatory drug (NSAID) selected from thegroup consisting of a salt of naproxen, and combinations thereof;wherein the amine-containing compound and the salt of an NSAID arewithin the hydrophilic matrix; wherein the composition exhibits arelease profile of the amine-containing compound comprising asubstantial portion that is representative of zero-order releasekinetics under in vitro conditions.

In a preferred embodiment, the present invention provides asustained-release oral pharmaceutical composition comprising within asingle dosage form: a hydrophilic matrix comprising a hydroxypropylmethylcellulose; a therapeutically effective amount of anamine-containing compound selected from the group consisting ofcyclobenzaprine, a salt thereof, and combinations thereof; and a salt ofa non-steroidal anti-inflammatory drug (NSAID) selected from the groupconsisting of a salt of naproxen, and combinations thereof; wherein theamine-containing compound or salt thereof and the salt of an NSAID arewithin the hydrophilic matrix; wherein the composition exhibits arelease profile of the amine-containing compound comprising asubstantial portion that is representative of zero-order releasekinetics under in vitro conditions.

In a preferred embodiment, the present invention provides asustained-release oral pharmaceutical composition comprising within asingle dosage foam: a hydrophilic matrix comprising a hydroxypropylmethylcellulose; a therapeutically effective amount of anamine-containing compound selected from the group consisting ofbenztropine, a salt thereof, and combinations thereof; and a salt of anon-steroidal anti-inflammatory drug (NSAID) selected from the groupconsisting of a salt of naproxen, and combinations thereof; wherein theamine-containing compound and the salt of an NSAID are within thehydrophilic matrix; wherein the composition exhibits a release profileof the amine-containing compound comprising a substantial portion thatis representative of zero-order release kinetics under in vitroconditions.

In a preferred embodiment, the present invention provides asustained-release oral pharmaceutical composition comprising within asingle dosage form: a hydrophilic matrix; a therapeutically effectiveamount of an amine-containing compound selected from the groupconsisting of dextromethorphan, cyclobenzaprine, benztropine, saltsthereof, and combinations thereof; a salt of a non-steroidalanti-inflammatory drug (NSAID) selected from the group consisting of asalt of naproxen, diclofenac, ibuprofen, and combinations thereof; and apharmaceutically acceptable anionic surfactant selected from the groupconsisting of sodium lauryl sulfate, docusate sodium, docusate calcium,and combinations thereof; wherein the amine-containing compound, thesalt of an NSAID, and the anionic surfactant are within the hydrophilicmatrix. Preferably, such composition exhibits a release profile of theamine-containing compound comprising a substantial portion that isrepresentative of zero-order release kinetics under in vitro conditions.

In a preferred embodiment, the present invention provides asustained-release oral pharmaceutical composition comprising within asingle dosage form: a hydrophilic matrix comprising a hydroxypropylmethylcellulose; a therapeutically effective amount of anamine-containing compound selected from the group consisting ofdextromethorphan, a salt thereof, and combinations thereof; a salt of anon-steroidal anti-inflammatory drug (NSAID) selected from the groupconsisting of a salt of naproxen, and combinations thereof; and apharmaceutically acceptable anionic surfactant selected from the groupconsisting of docusate sodium, docusate calcium, and combinationsthereof; wherein the amine-containing compound, the salt of an NSAID,and the anionic surfactant are within the hydrophilic matrix.Preferably, such composition exhibits a release profile of theamine-containing compound comprising a substantial portion that isrepresentative of zero-order release kinetics under in vitro conditions.

In a preferred embodiment, the present invention provides asustained-release oral pharmaceutical composition comprising within asingle dosage form: a hydrophilic matrix comprising a hydroxypropylmethylcellulose; a therapeutically effective amount of anamine-containing compound selected from the group consisting ofcyclobenzaprine, a salt thereof, and combinations thereof; a salt of anon-steroidal anti-inflammatory drug (NSAID) selected from the groupconsisting of a salt of naproxen, and combinations thereof; and apharmaceutically acceptable anionic surfactant selected from the groupconsisting of docusate sodium, docusate calcium, and combinationsthereof; wherein the amine-containing compound, the salt of an NSAID,and the anionic surfactant are within the hydrophilic matrix.Preferably, such composition exhibits a release profile of theamine-containing compound comprising a substantial portion that isrepresentative of zero-order release kinetics under in vitro conditions.

In a preferred embodiment, the present invention provides asustained-release oral pharmaceutical composition comprising within asingle dosage form: a hydrophilic matrix comprising a hydroxypropylmethylcellulose; a therapeutically effective amount of anamine-containing compound selected from the group consisting ofbenztropine, a salt thereof, and combinations thereof; a salt of anon-steroidal anti-inflammatory drug (NSAID) selected from the groupconsisting of a salt of naproxen, and combinations thereof; and apharmaceutically acceptable anionic surfactant selected from the groupconsisting of docusate sodium, docusate calcium, and combinationsthereof; wherein the amine-containing compound, the salt of an NSAID,and the anionic surfactant are within the hydrophilic matrix.Preferably, such composition exhibits a release profile of theamine-containing compound comprising a substantial portion that isrepresentative of zero-order release kinetics under in vitro conditions.

In a preferred embodiment, the present invention provides a method ofproviding a desired effect in a subject, the method administering to asubject a composition of any of the embodiments presented herein. Inmethods of the present invention, administering a composition of thepresent invention comprises administering once or twice per day, andoften once per day.

The terms “comprises” and variations thereof do not have a limitingmeaning where these terms appear in the description and claims.

The words “preferred” and “preferably” refer to embodiments of theinvention that may afford certain benefits, under certain circumstances.However, other embodiments may also be preferred, under the same orother circumstances. Furthermore, the recitation of one or morepreferred embodiments does not imply that other embodiments are notuseful, and is not intended to exclude other embodiments from the scopeof the invention.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably. Thus, for example, a composition comprising “a”salt of a non-steroidal anti-inflammatory drug can be interpreted tomean that the composition includes “one or more” non-steroidalanti-inflammatory drugs. Similarly, a composition comprising “a”pharmaceutically acceptable anionic surfactant can be interpreted tomean that the composition includes “one or more” pharmaceuticallyacceptable anionic surfactants.

As used herein, the term “or” is generally employed in its senseincluding “and/or” unless the content clearly dictates otherwise. Theterm “and/or” means one or all of the listed elements or a combinationof any two or more of the listed elements.

Also herein, all numbers are assumed to be modified by the term “about”and preferably by the term “exactly.” Notwithstanding that the numericalranges and parameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. All numerical values, however,inherently contain certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

Also herein, the recitations of numerical ranges by endpoints includeall numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2,2.75, 3, 3.80, 4, 5, etc.). Where a range of values is “up to” aparticular value, that value is included within the range.

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. In several places throughout the application,guidance is provided through lists of examples, which examples can beused in various combinations. In each instance, the recited list servesonly as a representative group and should not be interpreted as anexclusive list.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1-3 show dissolution profiles in phosphate buffer for certaindextromethorphan (DXM) formulations in accordance with embodiments ofthe present invention.

FIG. 4 shows dissolution profiles in phosphate buffer for certaincyclobenzaprine (CBP) formulation in accordance with embodiments of thepresent invention.

FIG. 5 shows dissolution profiles in phosphate buffer for certainbenztropine (BTP) formulations in accordance with embodiments of thepresent invention.

FIG. 6-8 show dissolution profiles in phosphate buffer for certain DXMformulations in accordance with embodiments of the present invention.

FIG. 9 shows dissolution profiles in acidic and hydroalcoholic media fora DXM formulation in accordance with the present invention.

FIG. 10 shows dissolution profiles in phosphate buffer for amantadinetablet formulations in accordance with embodiments of the presentinvention.

FIG. 11 shows dissolution profiles in phosphate buffer for memantinetablet formulations in accordance with embodiments of the presentinvention.

FIG. 12 shows dissolution profiles in phosphate buffer for ritodrinetablet formulations in accordance with embodiments of the presentinvention.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention provides sustained-release oral pharmaceuticalcompositions and methods of use. Preferably, such compositions are usedfor pain treatment, cough suppression, muscle relaxation, treatment ofmigraine headaches, spasms, convulsions, antihistamine effect, or otherindications. Such compositions are in a single dosage form and include apharmacologically active amine-containing compound (including saltsthereof), a salt of a non-steroidal anti-inflammatory drug (NSAID), anda hydrophilic matrix. Certain embodiments also include apharmaceutically acceptable anionic surfactant.

Herein, sustained-release compositions release the amine-containingcompound over a period of time greater than 60 minutes. Preferredsustained-release formulations demonstrate at least 60%, and morepreferably at least 80%, release of the amine-containing compound over adesired period (e.g., a period of 8 to 12 hours). If desired, however,the formulations of the present invention could be tailored to releasethe amine-containing compound over any period from 6 hours to 24 hoursor longer.

Particularly preferred sustained-release compositions of the presentinvention demonstrate a zero-order release profile with respect to theamine-containing compound under in vitro conditions, such as when testedin accordance with appropriate United States Pharmacopeia test methods.Herein, “zero-order” with respect to the amine-containing compound(including salts thereof) means a relatively constant rate of release(i.e., exhibiting a substantially linear release profile over a periodof time, preferably at least a few hours) of the amine-containingcompound. Although a small portion (e.g., the initial 30-60 minutes) ofthe release profile may not be zero-order (e.g., as in a formulationcontaining an immediate-release coating, or a bilayer or multi-layerformulation comprising an immediate-release layer), a substantialportion (e.g., several hours), and preferably a major portion, of therelease profile is representative of zero-order release kinetics.

Amine-Containing Compounds

The amine-containing compounds of the present invention arepharmacologically active compounds that include one or more amine groups(primary, secondary, tertiary amines, or combinations thereof). Incertain preferred embodiments, the amine-containing compound comprises atertiary amine. In certain embodiments, the amine-containing compoundcomprises a ring nitrogen that is a tertiary amine. In other preferredembodiments, the amine-containing compound comprises a tertiary amine ora secondary amine, or a combination thereof. In yet other embodiments,the amine-containing compound comprises two or more of a tertiary amine,a secondary amine, and a primary amine.

Typically, such amine-containing compounds are non-opioid compounds,which means that the compounds may be similar in structure to manyopioids, but is not generally understood to bind to opioid receptors inthe same way or at the same level as that of opioids. That is, suchcompounds are not typically characterized as opioids as they do not haveany significant amount of opioid activity. Furthermore, the term“compound” as used herein includes salts thereof.

An opioid is a chemical substance that works by binding to opioidreceptors, which are found principally in the central nervous system andthe gastrointestinal tract. The receptors in these two organ systemsmediate both the beneficial effects, and the undesirable side effects.There are three principal classes of opioid receptors, μ, κ, δ (mu,kappa, and delta), although up to seventeen have been reported, andinclude the ε, ι, λ, and ζ (Epsilon, Iota, Lambda and Zeta) receptors.There are three subtypes of μ receptor: μ₁ and μ₂, and the newlydiscovered μ₃. Another receptor of clinical importance is theopioid-receptor-like receptor 1 (ORL1), which is involved in painresponses as well as having a major role in the development of toleranceto μ-opioid agonists used as analgesics. An opioid can have agonistcharacteristics, antagonist characteristics, or both. Compounds used incompositions of the present invention may be similar in structure tomany opioids, but they are not generally understood to bind to opioidreceptors in the same way or at the same level as that of opioids. Thatis, although compounds used in the present invention include one or moreamine groups (which may be a primary, secondary, or tertiary amine), andcertain compounds used in the present invention include a tertiary aminenitrogen, which may include a ring nitrogen, such compounds used hereinare not typically characterized as opioids.

Various amine-containing compounds can be used in the practice of theinvention. Each of these compounds includes a tertiary amine as shown,wherein the amine nitrogen may or may not be within a ring:

Dextromethorphan (DXM or DM,(+)-3-methoxy-17-methyl-9α,13α,14α-morphinan) is an antitussive drugused primarily as a cough suppressant, for the temporary relief of coughcaused by minor throat and bronchial irritation (as commonly accompaniesthe common cold), as well as those resulting from inhaled irritants. Itsmechanism of action is as an NMDA receptor antagonist.

Cyclobenzaprine(3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine) isa muscle relaxant that works in the central nervous system by blockingnerve impulses sent to the brain. It is used to treat skeletal muscleconditions such as pain and muscle spasms. The mechanism of action isunknown, although some research indicates that it inhibits the uptake ofnorepinephrine and blocks 5-HT2A and 5-HT2C receptors. It is alsoprescribed as a sleep-aid.

Benztropine((3-endo)-3-(diphenylmethoxy)-8-methyl-8-azabicyclo[3.2.1]octane) is ananticholinergic drug principally used for the treatment of Parkinson'sdisease.

Other pharmacologically active amine-containing (non-opioid) compoundsthat may be useful in the practice of the present invention include thefollowing:

Such compounds function, for example, as muscle relaxants (baclofen,arbaclofen, ritodrine), antispasmodics (tizanidine), anticonvulsants(flurazepam), antihistamines (chlorpheniramine, doxylamine, anddiphenhydramine), as treatment and/or prevention agents for migraineheadaches (diltiazem), as antihypertensive agents (diltiazem),antivirals (rimantadine, amantadine), and/or as treatment of Parkinson'sDisease (rimantadine, amantadine) or Alzheimer's Disease (memantine).

Mixtures of suitable amine-containing compounds may also be employed inthe practice of the invention. That is, more than one pharmacologicallyactive amine-containing compound may be incorporated into one dosageform.

The amine-containing compounds can be used if desired in a variety ofsalt forms including “pharmaceutically acceptable salts.” Preparation ofsuch salts is known to those skilled in pharmaceuticals. Examples ofsuitable pharmaceutically acceptable salts include, but are not limitedto, hydrochlorides, bitartrates, acetates, naphthylates, tosylates,mesylates, besylates, succinates, palmitates, stearates, oleates,pamoates, laurates, valerates, hydrobromides, sulfates, methanesulfonates, tartrates, citrates, maleates, and the like, or combinationsof any of the foregoing.

In some suitable embodiments, the amine-containing compound is selectedfrom the group consisting of dextromethorphan (e.g., dextromethorphanhydrobromide), cyclobenzaprine (e.g., cyclobenzaprine hydrochloride),benztropine (e.g., benztropine mesylate) and combinations thereof. Forcertain embodiments, the amine-containing compound is dextromethorphan(particularly dextromethorphan hydrobromide). For certain embodiments,the amine-containing compound is cyclobenzaprine (particularlycyclobenzaprine hydrochloride). For certain embodiments, theamine-containing compound is benztropine (particularly benztropinemesylate).

An amine-containing compound is used herein in a therapeuticallyeffective amount to provide a desired effect. Determination of atherapeutically effective amount will be determined by the conditionbeing treated (e.g., pain, cough, spasms, migraine headaches, and thelike) and on the target dosing regimen (e.g., once per day, twice perday). Determination of such an amount is well within the capability ofthose skilled in the art, especially in light of the detailed disclosureprovided herein. For example, if the composition is used as a coughsuppressant, the amount of an amine-containing compound would be thatwhich is effective for suppressing a cough. If the composition is usedto treat pain, for example, a therapeutically effective amount of anamine-containing compound is referred to herein as a “pain-reducingamount.” Herein, this means an amount of compound effective to reduce ortreat (i.e., prevent, alleviate, or ameliorate) symptoms over thedesired time period. This amount can vary with each specificamine-containing compound depending on the potency of each. For example,the amount per single dosage form of the present invention may be 5 mgto 50 mg.

Salts of Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Compositions of the present invention include one or more non-steroidalanti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs. Theseare drugs with analgesic, antipyretic and, in higher doses,anti-inflammatory effects. NSAIDs are sometimes also referred to asnon-steroidal anti-inflammatory agents/analgesics (NSAIAs) ornon-steroidal anti-inflammatory medicines (NSAIMs). All NSAIDs as usedherein are nonspecific COX inhibitors.

Surprisingly, in the practice of the present invention, salts of NSAIDs(but not the free bases) provide compositions with zero-order releasekinetics with respect to the amine-containing compounds (including saltsthereof).

There are roughly seven major classes of NSAIDs, including:

(1) salicylate derivatives, such as acetylsalicylic acid (aspirin),amoxiprin, benorylate/benorilate, choline magnesium salicylate,diflunisal, ethenzamide, faislamine, methyl salicylate, magnesiumsalicylate, salicyl salicylate, and salicylamide; a few structures ofsuch compounds are as follows:

(2) 2-aryl propionic acid derivatives, such as ibuprofen, ketoprofen,alminoprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen,fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, ondoprofen,ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, andtiaprofenic acid; a few structures of such compounds are as follows:

(3) pyrazolidine derivatives, such as phenylbutazone, ampyrone,azapropazone, clofezone, kebuzone, metamizole, mofebutazone,oxyphenbutazone, phenazone, and sulfinpyrazone; a few structures of suchcompounds are as follows:

(4) N-arylanthranilic acid (or fenamate) derivatives, such as mefenamicacid, flufenamic acid, meclofenamic acid, tolfenamic acid, and estersthereof; a few structures of such compounds are as follows:

(5) oxicam derivatives, such as piroxicam, droxicam, lornoxicam,meloxicam, and tenoxicam; a few structures of such compounds are asfollows:

(6) arylalkanoic acids, such as diclofenac, aceclofenac, acemethacin,alclofenac, bromfenac, etodolac, indomethacin, nabumetone, oxametacin,proglumetacin, sulindac (prodrug), and tolmetin; a few structures ofsuch compounds are as follows:

(7) indole derivatives, such as indomethacin, the structure of which isas follows:

Although acetaminophen (paracetamol) is an analgesic and it is sometimesgrouped with NSAIDs, it is not an NSAID (particularly for the purposesof the present invention) because it does not have any significantanti-inflammatory activity.

NSAIDs used in compositions of the present invention arepharmaceutically acceptable salts thereof. Typically, such salts includemetal salts, such as sodium, calcium, or potassium salts. Salts such asbismuth salts, magnesium salts, or zinc salts may also be suitable.Various combinations of counterions and/or NSAID salts can be used ifdesired.

Preferred NSAID salts include a terminal carboxylic acid or terminalcarboxylate group on the active moiety. In certain embodiments, theNSAID salts include a terminal carboxylic acid group on the activemoiety. In certain embodiments, the NSAID salts include a terminalcarboxylate group on the active moiety. Exemplary such NSAID salts areselected from the group consisting of a salicylate derivative, a 2-arylpropionic acid derivative, an N-arylanthranilic acid derivative, an arylalkanoic acid, an indole derivative, and combinations thereof. PreferredNSAID salts include salts of 2-aryl propionic acid derivative (e.g.,naproxen and ibuprofen), aryl alkanoic acids, or combinations thereof.Particularly preferred NSAID salts include naproxen sodium, ibuprofensodium, diclofenac sodium, and combinations thereof. Structures ofnaproxen, diclofenac, and ibuprofen are as follows:

In preferred compositions, an NSAID salt is present in an amount toprovide zero-order release kinetics with respect to the amine-containingcompound under in vitro conditions. Such amount can be a sub-therapeuticamount or it can be a conventional therapeutic amount. Determination ofsuch an amount is well within the capability of those skilled in theart, especially in light of the detailed disclosure provided herein. Forexample, naproxen sodium could be included in a single dosage faun ofthe current invention at an amount of 220 mg to 750 mg (for atwice-per-day dosage form).

Pharmaceutically Acceptable Anionic Surfactants

Suitable pharmaceutically acceptable anionic surfactants could include,for example, monovalent alkyl carboxylates, acyl lactylates, alkyl ethercarboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acylglutamates, fatty acid-polypeptide condensates, sulfur-containingsurfactants (e.g., sulfuric acid esters, alkyl sulfates such as sodiumlauryl sulfate (SLS), ethoxylated alkyl sulfates, ester linkedsulfonates such as docusate sodium or dioctyl sodium succinate (DSS),and alpha olefin sulfonates), and phosphated ethoxylated alcohols.Preferred surfactants are on the GRAS (“Generally Recognized as Safe”)list. Various combinations of pharmaceutically acceptable anionicsurfactants can be used if desired.

In certain embodiments, the pharmaceutically acceptable anionicsurfactant is a sulfur-containing surfactant, and particularly an alkylsulfate, an ester-linked sulfonate, and combinations thereof. Preferredpharmaceutically acceptable anionic surfactants include sodium laurylsulfate, docusate (i.e., dioctyl sulfosuccinate) sodium, docusatecalcium, and combinations thereof. A particularly preferred anionicsurfactant is docusate sodium. The structures of docusate sodium andsodium lauryl sulfate are as follows:

In preferred embodiments, a pharmaceutically acceptable anionicsurfactant is present in compositions of the present invention in arelease-modifying amount. A wide range of amounts can be used to tailorthe rate and extent of release. Determination of such an amount is wellwithin the capability of those skilled in the art, especially in lightof the detailed disclosure provided herein.

In some embodiments, certain surfactants such as docusate can functionas a stool softener when used at a therapeutic level; however,sub-therapeutic amounts can be used for release modification.

Such surfactants can be used for their abuse deterrence effects. Forexample, a surfactant could function as a nasal irritant, which wouldmake crushing and inhaling the compositions undesirable. Also, a mixtureof a non-opioid amine-containing compound and a surfactant (e.g.,docusate) in a hydrophilic matrix is difficult to extract and separateinto the individual components, and injection of the mixture isundesirable and/or unsafe.

Hydrophilic Matrix and Other Excipients

Compositions of the present invention include a hydrophilic matrix,wherein the amine-containing compound (including salt thereof), the saltof an NSAID, and the optional anionic surfactant are within (e.g., mixedwithin) the hydrophilic matrix. Such matrix preferably includes at leastone hydrophilic polymeric compound. The hydrophilic polymeric compoundpreferably forms a matrix that releases the amine-containing compound(including a pharmaceutically acceptable salt thereof) at a sustainedrate upon exposure to liquids. The rate of release of theamine-containing compound (including a pharmaceutically acceptable saltthereof) from the hydrophilic matrix typically depends, at least inpart, on the amine-containing compound's partition coefficient betweenthe components of the hydrophilic matrix and the aqueous phase withinthe gastrointestinal tract.

The sustained-release composition generally includes at least onehydrophilic polymeric compound in an amount of 10% to 90% by weight,preferably in an amount of 20% to 80% by weight, based on the totalweight of the composition.

The hydrophilic polymeric compound may be any known in the art.Exemplary hydrophilic polymeric compounds include gums, celluloseethers, acrylic resins, polyvinyl pyrrolidone, protein-derivedcompounds, and combinations thereof. Exemplary gums includeheteropolysaccharide gums and homopolysaccharide gums, such as xanthan,tragacanth, pectins, acacia, karaya, alginates, agar, guar,hydroxypropyl guar, carrageenan, locust bean gums, and gellan gums.Exemplary cellulose ethers include hydroxyalkyl celluloses andcarboxyalkyl celluloses. Preferred cellulose ethers include hydroxyethylcelluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses,carboxymethylcelluloses, and mixtures thereof. Exemplary acrylic resinsinclude polymers and copolymers of acrylic acid, methacrylic acid,methyl acrylate, and methyl methacrylate. Various combinations ofhydrophilic compounds can be used for various effects.

In some embodiments, the hydrophilic compound is preferably a celluloseether. Exemplary cellulose ethers include those commercially availableunder the trade designation METHOCEL Premium from Dow Chemical Co. Suchmethylcellulose and hypromellose (i.e., hydroxypropyl methylcellulose)products are a broad range of water-soluble cellulose ethers that enablepharmaceutical developers to create formulas for tablet coatings,granulation, sustained release, extrusion, and molding. For certainembodiments, the cellulose ether comprises a hydroxypropylmethylcellulose.

Varying the types of cellulose ethers can impact the release rate. Forexample, varying the types of METHOCEL cellulose ethers, which havedifferent viscosities of 2% solutions in water (METHOCEL K4M Premiumhypromellose 2208 (19-24% methoxy content; 7-12% hydroxypropyl content;3,000-5,600 cps of a 2% solution in water); METHOCEL K15M Premiumhypromellose 2208 (19-24% methoxy content; 7-12% hydroxypropyl content;11,250-21,000 cps of a 2% solution in water); and METHOCEL K100M Premiumhypromellose 2208 (19-24% methoxy content; 7-12% hydroxypropyl content;80,000-120,000 cps of a 2% solution in water)) can help tailor releaserates.

Compositions of the present invention can also include one or moreexcipients such as lubricants, glidants, flavorants, coloring agents,stabilizers, binders, fillers, disintegrants, diluents, suspendingagents, viscosity enhancers, wetting agents, buffering agents, controlrelease agents, crosslinking agents, preservatives, and the like. Suchcompounds are well known in the art of drug release and can be used invarious combinations.

One particularly useful excipient that can form at least a portion of acomposition of the present invention is a binder that includes, forexample, a cellulose such as microcrystalline cellulose. An exemplarymicrocrystalline cellulose is that available under the trade designationAVICEL PH (e.g., AVICEL PH-101, AVICEL PH-102, AVICEL PH-301, AVICELPH-302, and AVICEL RC-591) from FMC BioPolymers. The sustained-releasecomposition generally includes at least one microcrystalline cellulosein an amount of 3 wt-% to 50 wt-%, based on the total weight of thecomposition.

Other additives can be incorporated into compositions of the presentinvention to further modify the rate and extent of release. For example,a non-pharmacologically active amine, such as tromethamine,triethanolamine, betaine, benzathine, or erbumine could be included inthe compositions of the present invention to further modify the releaserate.

Compositions of the present invention can optionally include compoundsthat function as abuse deterrents. For example, compounds that causenausea could be added to the formulation containing, for example, DXM,to prevent abusers from taking more than the intended dose. Thesecomponents are added to the formulation at sub-therapeutic levels, suchthat no adverse effects are realized when the correct dose is taken.

Also, compositions of the present invention can include an aversiveagent such as a dye (e.g., one that stains the mucous membrane of thenose and/or mouth) that is released when the dosage form is tamperedwith and provides a noticeable color or dye which makes the act of abusevisible to the abuser and to others such that the abuser is less likelyto inhale, inject, and/or swallow the tampered dosage form. Examples ofvarious dyes that can be employed as the aversive agent, including forexample, and without limitation, FD&C Red No. 3, FD&C Red No. 20, FD&CYellow No. 6, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Green No. 1, FD&CGreen No. 3, FD&C Green No. 5, FD&C Red No. 30, D&C Orange No. 5, D&CRed No. 8, D&C Red No. 33, caramel, and ferric oxide, red, other FD&Cdyes and lakes, and natural coloring agents such as grape skin extract,beet red powder, beta-carotene, annato, carmine, turmeric, paprika, andcombinations thereof.

The sustained-release compositions of the present invention may alsoinclude one or more hydrophobic polymers. The hydrophobic polymers maybe used in an amount sufficient to slow the hydration of the hydrophiliccompound without disrupting it. For example, the hydrophobic polymer maybe present in an amount of 0.5% to 20% by weight, based on the totalweight of the composition.

Exemplary hydrophobic polymers include alkyl celluloses (e.g., C₁₋₆alkyl celluloses, carboxymethylcellulose, ethylcellulose), otherhydrophobic cellulosic materials or compounds (e.g., cellulose acetatephthalate, hydroxypropylmethylcellulose phthalate), polyvinyl acetatepolymers (e.g., polyvinyl acetate phthalate), polymers or copolymersderived from acrylic and/or methacrylic acid esters, zein, waxes (e.g.,carnauba wax), shellac, hydrogenated vegetable oils, and combinationsthereof.

Pharmaceutical Compositions

Pharmaceutical compositions of the present invention are single dosageforms that can be in a form capable of providing sustained release of anamine-containing compound. Herein, a “single dosage form” refers to thecomponents of the composition included within one physical unit (e.g.,one tablet), whether it be in a uniform matrix, a multilayeredconstruction, or some other configuration. Most commonly, this includesa tablet, which can include molded tablets, compressed tablets, orfreeze-dried tablets. Other possible solid forms include pills, pellets,particulate forms (e.g., beads, powders, granules), and capsules (e.g.,with particulate therein).

A single dosage form can be a coated dosage form with, for example, anouter layer of an immediate-release (IR) material (e.g., anamine-containing compound, an NSAID, or both, a release-modifying agent,a film coating for taste masking or for ease of swallowing, or thelike), with a sustained-release (SR) core. Typically, such coatedformulations do not demonstrate zero-order release kinetics during aninitial immediate-release phase, but preferably demonstrate zero-orderrelease kinetics with respect to the amine-containing compound duringthe dissolution of the sustained-release core.

A single dosage form can be incorporated into a multi-layered dosageform (e.g., tablet). For example, a bilayer tablet could be formulatedto include a layer of a conventional immediate-release matrix and alayer of a sustained-release composition of the present invention.Optionally, a multi-layered dosage form could be coated.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner to incorporate one ormore physiologically acceptable carriers comprising excipients andauxiliaries. Compositions of the invention may be formulated as tablets,pills, capsules, and the like, for oral ingestion by a patient to betreated.

Pharmaceutical compositions of the present invention may be manufacturedin a manner that is itself known, e.g., by means of conventional mixing,granulating, encapsulating, entrapping, or tabletting processes.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions where the ingredients are contained in an amounteffective to achieve its intended purpose. The exact formulation, routeof administration, and dosage for the pharmaceutical compositions of thepresent invention can be chosen by the individual physician in view ofthe patient's condition. (See, e.g., Fingl et al. in “ThePharmacological Basis of Therapeutics”, Ch. 1, p. 1 (1975)). The exactdosage will be determined on a drug-by-drug basis, in most cases. Dosageamount and interval may be adjusted individually to provide plasmalevels of the active ingredients/moieties that are sufficient tomaintain the modulating effects, or minimal effective concentration(MEC). The MEC will vary for each compound but can be estimated from invitro data. Dosages necessary to achieve the MEC will depend onindividual characteristics and route of administration. However, HPLCassays or bioassays can be used to determine plasma concentrations. Theamount of composition administered will, of course, be dependent on thesubject being treated, on the subject's weight, the severity of thesymptoms (e.g., pain, cough, spasms, etc.), the manner ofadministration, and the judgment of the prescribing physician.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert.

It will be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present invention. Therefore, it should be clearly understood thatthe forms of the present invention are illustrative only and are notintended to limit the scope of the present invention.

Exemplary Embodiments of the Invention

1. A sustained-release oral pharmaceutical composition comprising withina single dosage form:

-   -   a hydrophilic matrix;    -   a therapeutically effective amount of a non-opioid        amine-containing compound; and    -   a salt of a non-steroidal anti-inflammatory drug (NSAID);    -   wherein the amine-containing compound and the salt of an NSAID        are within the hydrophilic matrix; and    -   wherein the composition exhibits a release profile of the        amine-containing compound comprising a substantial portion that        is representative of zero-order release kinetics under in vitro        conditions.        2. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix;    -   a therapeutically effective amount of a non-opioid        amine-containing compound;    -   a salt of a non-steroidal anti-inflammatory drug (NSAID); and    -   a pharmaceutically acceptable anionic surfactant;    -   wherein the amine-containing compound, the salt of an NSAID, and        the anionic surfactant are within the hydrophilic matrix.        3. The composition of embodiment 2 which exhibits a release        profile of the amine-containing compound comprising a        substantial portion that is representative of zero-order release        kinetics under in vitro conditions.        4. The composition of any one of embodiments 1 through 3 wherein        the amine group comprises a secondary amine, a tertiary amine, a        primary amine, or combination thereof.        5. The composition of embodiment 4 wherein the amine-containing        compound comprises a tertiary amine.        6. The composition of embodiment 4 wherein the amine-containing        compound comprises a primary amine.        7. The composition of embodiment 4 wherein the amine-containing        compound comprises a secondary amine.        8. The composition of any one of embodiments 1 through 4 wherein        the amine-containing compound is selected from the group        consisting of dextromethorphan, cyclobenzaprine, benztropine,        baclofen, arbaclofen, ritodrine, tizanidine, flurazepam,        chlorpheniramine, doxylamine, diphenhydramine, diltiazem,        rimantadine, amantadine, memantine, and combinations thereof.        9. The composition of any one of embodiments 1 through 8 wherein        the amine-containing compound salt comprises a hydrochloride, a        bitartrate, an acetate, a naphthylate, a tosylate, a mesylate, a        besylate, a succinate, a palmitate, a stearate, an oleate, a        pamoate, a laurate, a valerate, a hydrobromide, a sulfate, a        methane sulfonate, a tartrate, a citrate, a maleate, or a        combination of the foregoing.        10. The composition of embodiment 8 or embodiment 9 wherein the        amine-containing compound is selected from the group consisting        of dextromethorphan, cyclobenzaprine, benztropine, ritodrine,        memantine, amantadine, salts thereof, and combinations thereof.        11. The composition of embodiment 8 wherein the amine-containing        compound is selected from the group consisting of        dextromethorphan hydrobromide, cyclobenzaprine hydrochloride,        benztropine mesylate, ritodrine hydrochloride, memantine        hydrochloride, amantadine hydrochloride, and combinations        thereof.        12. The composition of any one of embodiments 8 through 10        wherein the amine-containing compound is selected from the group        consisting of dextromethorphan, a salt thereof, and combinations        thereof.        13. The composition of embodiment 12 wherein the        amine-containing compound comprises dextromethorphan        hydrobromide.        14. The composition of any one of embodiments 8 through 10        wherein the amine-containing compound is selected from the group        consisting of cyclobenzaprine, a salt thereof, and combinations        thereof.        15. The composition of embodiment 14 wherein the        amine-containing compound comprises cyclobenzaprine        hydrochloride.        16. The composition of any one of embodiments 8 through 10        wherein the amine-containing compound is selected from the group        consisting of benztropine, a salt thereof, and combinations        thereof.        17. The composition of embodiment 16 wherein the        amine-containing compound comprises benztropine mesylate.        18. The composition of any one of embodiments 8 through 10        wherein the amine-containing compound is selected from the group        consisting of ritodrine, a salt thereof, and combinations        thereof.        19. The composition of embodiment 18 wherein the        amine-containing compound comprises ritodrine hydrochloride.        20. The composition of any one of embodiments 8 through 10        wherein the amine-containing compound is selected from the group        consisting of memantine, a salt thereof, and combinations        thereof.        21. The composition of embodiment 20 wherein the        amine-containing compound comprises memantine hydrochloride.        22. The composition of any one of embodiments 8 through 10        wherein the amine-containing compound is selected from the group        consisting of amantadine, a salt thereof, and combinations        thereof.        23. The composition of embodiment 18 wherein the        amine-containing compound comprises amantadine hydrochloride.        24. The composition of any one of the preceding embodiments        wherein the NSAID salt is selected from the group consisting of        a salicylate derivative, a 2-aryl propionic acid derivative, a        pyrazolidine derivative, an N-arylanthranilic acid derivative,        an oxicam derivative, an arylalkanoic acid, an indole        derivative, and combinations thereof.        25. The composition of embodiment 24 wherein the NSAID salt        comprises a terminal carboxylic acid group or terminal        carboxylate group.        26. The composition of embodiment 25 wherein the NSAID salt is        selected from the group consisting of a salicylate derivative, a        2-aryl propionic acid derivative, an N-arylanthranilic acid        derivative, an aryl alkanoic acid, an indole derivative, and        combinations thereof.        27. The composition of embodiment 26 wherein the NSAID salt is a        2-aryl propionic acid derivative, an aryl alkanoic acid, or        combinations thereof.        28. The composition of embodiment 27 wherein the NSAID salt is        selected from the group consisting of a salt of naproxen,        diclofenac, ibuprofen, and combinations thereof.        29. The composition of embodiment 28 wherein the NSAID salt is        selected from the group consisting of naproxen sodium,        diclofenac sodium, ibuprofen sodium, and combinations thereof.        30. The composition of any one of embodiments 2 through 29, as        they depend on embodiment 2, wherein the pharmaceutically        acceptable anionic surfactant is selected from the group        consisting of monovalent alkyl carboxylates, acyl lactylates,        alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl        carbonates, N-acyl glutamates, fatty acid-polypeptide        condensates, sulfur-containing surfactants, phosphated        ethoxylated alcohols, and combinations thereof.        31. The composition of embodiment 30 wherein the        pharmaceutically acceptable anionic surfactant is a        sulfur-containing surfactant.        32. The composition of embodiment 31 wherein the        sulfur-containing surfactant is selected from the group        consisting of an alkyl sulfate, an ester-linked sulfonate, and        combinations thereof.        33. The composition of embodiment 32 wherein the        pharmaceutically acceptable anionic surfactant is selected from        the group consisting of sodium lauryl sulfate, docusate sodium,        docusate calcium, and combinations thereof.        34. The composition of embodiment 33 wherein the        pharmaceutically acceptable anionic surfactant is docusate        sodium.        35. The composition of any one of the preceding embodiments        wherein the NSAID salt is present in an amount effective to        provide zero-order release kinetics under in vitro conditions.        36. The composition of any one of the preceding embodiments        wherein the pharmaceutically acceptable anionic surfactant is        present in a release-modifying amount.        37. The composition of any one of the preceding embodiments        wherein the single dosage form is a tablet form.        38. The composition of embodiment 37 wherein the single dosage        form tablet comprises a unitary matrix.        39. The composition of embodiment 37 wherein the single dosage        fowl tablet comprises a multilayer tablet.        40. The composition of embodiment 39 wherein the single dosage        form comprises an outer layer of an immediate-release (IR)        material and a sustained-release (SR) core.        41. The composition of embodiment 40 wherein the IR material        comprises an amine-containing compound, an NSAID, or both.        42. The composition of any one of the previous embodiments        wherein the hydrophilic matrix comprises at least one        hydrophilic polymeric compound selected from the group        consisting of a gum, a cellulose ether, an acrylic resin, a        polyvinyl pyrrolidone, a protein-derived compound, and        combinations thereof.        43. The composition of embodiment 42 wherein the hydrophilic        polymeric compound comprises a cellulose ether.        44. The composition of embodiment 43 wherein the cellulose ether        comprises a hydroxyalkyl cellulose, a carboxyalkyl cellulose,        and combinations thereof.        45. The composition of embodiment 44 wherein the cellulose ether        comprises a methylcellulose, a hydroxypropyl methylcellulose,        and combinations thereof.        46. The composition of embodiment 45 wherein the cellulose ether        comprises a hydroxypropyl methylcellulose.        47. The composition of any one of the previous embodiments        further including one or more excipients.        48. The composition of embodiment 47 wherein the excipients        comprise lubricants, glidants, flavorants, coloring agents,        stabilizers, binders, fillers, disintegrants, diluents,        suspending agents, viscosity enhancers, wetting agents,        buffering agents, control release agents, crosslinking agents,        preservatives, and combinations thereof.        49. The composition of embodiment 48 comprising a binder.        50. The composition of embodiment 49 wherein the binder        comprises a microcrystalline cellulose.        51. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of dextromethorphan,        cyclobenzaprine, benztropine, ritodrine, memantine, amantadine,        salts thereof, and combinations thereof; and    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen,        diclofenac, ibuprofen, and combinations thereof;    -   wherein the amine-containing compound and the salt of an NSAID        are within the hydrophilic matrix; and    -   wherein the composition exhibits a release profile of the        amine-containing compound comprising a substantial portion that        is representative of zero-order release kinetics under in vitro        conditions.        52. The composition of embodiment 51 wherein the        amine-containing compound is selected from the group consisting        of dextromethorphan, a salt thereof, and combinations thereof.        53. The composition of embodiment 52 wherein the        amine-containing compound comprises dextromethorphan        hydrobromide.        54. The composition of embodiment 51 wherein the        amine-containing compound is selected from the group consisting        of cyclobenzaprine, a salt thereof; and combinations thereof.        55. The composition of embodiment 54 wherein the        amine-containing compound comprises cyclobenzaprine        hydrochloride.        56. The composition of embodiment 51 wherein the        amine-containing compound is selected from the group consisting        of benztropine, a salt thereof; and combinations thereof.        57. The composition of embodiment 56 wherein the        amine-containing compound comprises benztropine mesylate.        58. The composition of embodiment 51 wherein the        amine-containing compound is selected from the group consisting        of ritodrine, a salt thereof, and combinations thereof.        59. The composition of embodiment 58 wherein the        amine-containing compound comprises ritodrine hydrochloride.        60. The composition of embodiment 51 wherein the        amine-containing compound is selected from the group consisting        of memantine, a salt thereof, and combinations thereof.        61. The composition of embodiment 60 wherein the        amine-containing compound comprises memantine hydrochloride.        62. The composition of embodiment 51 wherein the        amine-containing compound is selected from the group consisting        of amantadine, a salt thereof, and combinations thereof.        63. The composition of embodiment 62 wherein the        amine-containing compound comprises amantadine hydrochloride.        64. The composition of any one of embodiments 51 through 63        wherein the NSAID salt is selected from the group consisting of        naproxen sodium, diclofenac sodium, ibuprofen sodium, and        combinations thereof.        65. The composition of any one of embodiments 51 through 64        wherein the hydrophilic polymeric compound comprises a cellulose        ether.        66. The composition of embodiment 65 wherein the cellulose ether        comprises a hydroxyalkyl cellulose, a carboxyalkyl cellulose,        and combinations thereof.        67. The composition of embodiment 65 wherein the cellulose ether        comprises a methylcellulose, a hydroxypropyl methylcellulose,        and combinations thereof.        68. The composition of embodiment 65 wherein the cellulose ether        comprises a hydroxypropyl methylcellulose.        69. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix comprising a hydroxypropyl methylcellulose;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of dextromethorphan,        a salt thereof, and combinations thereof; and    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen, and        combinations thereof;    -   wherein the amine-containing compound and the salt of an NSAID        are within the hydrophilic matrix; and    -   wherein the composition exhibits a release profile of the        amine-containing compound comprising a substantial portion that        is representative of zero-order release kinetics under in vitro        conditions.        70. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix comprising a hydroxypropyl methylcellulose;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of cyclobenzaprine,        a salt thereof, and combinations thereof; and    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen, and        combinations thereof;    -   wherein the amine-containing compound and the salt of an NSAID        are within the hydrophilic matrix; and    -   wherein the composition exhibits a release profile of the        amine-containing compound comprising a substantial portion that        is representative of zero-order release kinetics under in vitro        conditions.        71. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix comprising a hydroxypropyl methylcellulose;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of benztropine, a        salt thereof; and combinations thereof; and    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen, and        combinations thereof;    -   wherein the amine-containing compound and the salt of an NSAID        are within the hydrophilic matrix; and    -   wherein the composition exhibits a release profile of the        amine-containing compound comprising a substantial portion that        is representative of zero-order release kinetics under in vitro        conditions.        72. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix comprising a hydroxypropyl methylcellulose;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of ritodrine, a salt        thereof, and combinations thereof; and    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen, and        combinations thereof;    -   wherein the amine-containing compound and the salt of an NSAID        are within the hydrophilic matrix; and    -   wherein the composition exhibits a release profile of the        amine-containing compound comprising a substantial portion that        is representative of zero-order release kinetics under in vitro        conditions.        73. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix comprising a hydroxypropyl methylcellulose;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of memantine, a salt        thereof, and combinations thereof; and    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen, and        combinations thereof;    -   wherein the amine-containing compound and the salt of an NSAID        are within the hydrophilic matrix; and    -   wherein the composition exhibits a release profile of the        amine-containing compound comprising a substantial portion that        is representative of zero-order release kinetics under in vitro        conditions.        74. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix comprising a hydroxypropyl methylcellulose;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of amantadine, a        salt thereof, and combinations thereof; and    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen, and        combinations thereof;    -   wherein the amine-containing compound and the salt of an NSAID        are within the hydrophilic matrix; and    -   wherein the composition exhibits a release profile of the        amine-containing compound comprising a substantial portion that        is representative of zero-order release kinetics under in vitro        conditions.        75. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of dextromethorphan,        cyclobenzaprine, benztropine, ritodrine, mamantine, amantadine,        salts thereof, and combinations thereof;    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen,        diclofenac, ibuprofen, and combinations thereof; and    -   a pharmaceutically acceptable anionic surfactant selected from        the group consisting of sodium lauryl sulfate, docusate sodium,        docusate calcium, and combinations thereof;    -   wherein the amine-containing compound the salt of an NSAID, and        the anionic surfactant are within the hydrophilic matrix.        76. The composition of embodiment 75 which exhibits a release        profile of the amine-containing compound comprising a        substantial portion that is representative of zero-order release        kinetics under in vitro conditions.        77. The composition of embodiment 75 or embodiment 76 wherein        the amine-containing compound is selected from the group        consisting of dextromethorphan, a salt thereof, and combinations        thereof.        78. The composition of embodiment 77 wherein the        amine-containing compound comprises dextromethorphan        hydrobromide.        79. The composition of embodiment 75 or embodiment 76 wherein        the amine-containing compound is selected from the group        consisting of cyclobenzaprine, a salt thereof, and combinations        thereof.        80. The composition of embodiment 79 wherein the        amine-containing compound comprises cyclobenzaprine        hydrochloride.        81. The composition of embodiment 75 or embodiment 76 wherein        the amine-containing compound is selected from the group        consisting of benztropine, a salt thereof, and combinations        thereof.        82. The composition of embodiment 81 wherein the        amine-containing compound comprises benztropine mesylate.        83. The composition of embodiment 75 or embodiment 76 wherein        the amine-containing compound is selected from the group        consisting of ritodrine, a salt thereof, and combinations        thereof.        84. The composition of embodiment 83 wherein the        amine-containing compound comprises ritodrine hydrochloride.        85. The composition of embodiment 75 or embodiment 76 wherein        the amine-containing compound is selected from the group        consisting of memantine, a salt thereof, and combinations        thereof.        86. The composition of embodiment 85 wherein the        amine-containing compound comprises memantine hydrochloride.        87. The composition of embodiment 75 or embodiment 76 wherein        the amine-containing compound is selected from the group        consisting of amantadine, a salt thereof, and combinations        thereof.        88. The composition of embodiment 87 wherein the        amine-containing compound comprises amantadine hydrochloride.        89. The composition of any one of embodiments 75 through 88        wherein the pharmaceutically acceptable anionic surfactant is        docusate sodium.        90. The composition of any one of embodiments 75 through 89        wherein the hydrophilic polymeric compound comprises a cellulose        ether.        91. The composition of embodiment 90 wherein the cellulose ether        comprises a hydroxyalkyl cellulose, a carboxyalkyl cellulose,        and combinations thereof.        92. The composition of embodiment 90 wherein the cellulose ether        comprises a methylcellulose, a hydroxypropyl methylcellulose,        and combinations thereof.        93. The composition of embodiment 90 wherein the cellulose ether        comprises a hydroxypropyl methylcellulose.        94. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix comprising a hydroxypropyl methylcellulose;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of dextromethorphan,        a salt thereof, and combinations thereof;    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen, and        combinations thereof; and    -   a pharmaceutically acceptable anionic surfactant selected from        the group consisting of docusate sodium, docusate calcium, and        combinations thereof;    -   wherein the amine-containing compound, the salt of an NSA/D, and        the anionic surfactant are within the hydrophilic matrix.        95. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix comprising a hydroxypropyl methylcellulose;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of cyclobenzaprine,        a salt thereof, and combinations thereof;    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen, and        combinations thereof; and    -   a pharmaceutically acceptable anionic surfactant selected from        the group consisting of docusate sodium, docusate calcium, and        combinations thereof;    -   wherein the amine-containing compound, the salt of an NSAID, and        the anionic surfactant are within the hydrophilic matrix.        96. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix comprising a hydroxypropyl methylcellulose;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of benztropine, a        salt thereof, and combinations thereof;    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen, and        combinations thereof; and    -   a pharmaceutically acceptable anionic surfactant selected from        the group consisting of docusate sodium, docusate calcium, and        combinations thereof;    -   wherein the amine-containing compound, the salt of an NSAID, and        the anionic surfactant are within the hydrophilic matrix.        97. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix comprising a hydroxypropyl methylcellulose;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of ritodrine, a salt        thereof, and combinations thereof;    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen, and        combinations thereof; and    -   a pharmaceutically acceptable anionic surfactant selected from        the group consisting of docusate sodium, docusate calcium, and        combinations thereof;    -   wherein the amine-containing compound, the salt of an NSAID, and        the anionic surfactant are within the hydrophilic matrix.        98. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix comprising a hydroxypropyl methylcellulose;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of memantine, a salt        thereof, and combinations thereof;    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen, and        combinations thereof; and    -   a pharmaceutically acceptable anionic surfactant selected from        the group consisting of docusate sodium, docusate calcium, and        combinations thereof;    -   wherein the amine-containing compound, the salt of an NSAID, and        the anionic surfactant are within the hydrophilic matrix.        99. A sustained-release oral pharmaceutical composition        comprising within a single dosage form:    -   a hydrophilic matrix comprising a hydroxypropyl methylcellulose;    -   a therapeutically effective amount of an amine-containing        compound selected from the group consisting of amantadine, a        salt thereof, and combinations thereof;    -   a salt of a non-steroidal anti-inflammatory drug (NSAID)        selected from the group consisting of a salt of naproxen, and        combinations thereof; and    -   a pharmaceutically acceptable anionic surfactant selected from        the group consisting of docusate sodium, docusate calcium, and        combinations thereof;    -   wherein the amine-containing compound, the salt of an NSAID, and        the anionic surfactant are within the hydrophilic matrix.        100. The composition of any one of embodiments 94 through 99        which exhibits a release profile of the amine-containing        compound comprising a substantial portion that is representative        of zero-order release kinetics under in vitro conditions.        101. A method of providing a desired effect in a subject, the        method comprising administering to a subject a composition of        any one of embodiments 1 through 100.        102. The method of embodiment 101 wherein administering the        composition comprises administering once or twice per day.        103. The method of embodiment 102 wherein administering the        composition comprises administering once per day.

EXAMPLES

Objects and advantages of this invention are further illustrated by thefollowing examples, but the particular materials and amounts thereofrecited in these examples, as well as other conditions and details,should not be construed to unduly limit this invention.

Sources for materials used in the following Examples are as follows:

Component Vendor Dextromethorphan Hydrobromide Wockhardt LimitedMethocel K4M Dow Chemical Avicel PH-302 FMC Biopolymer Naproxen SodiumAlbemarle Corp. Naproxen Sigma-Aldrich, Inc. Ibuprofen SodiumSigma-Aldrich, Inc. Ibuprofen Sigma-Aldrich, Inc. Docusate Sodium CytecIndustries, Inc. Benztropine Mesylate Spectrum Chemical Sodium LaurylSulfate Fisher Scientific Ritodrine HCl Sigma-Aldrich

Example 1 Preparation of Sustained-release Hydrophilic Matrix TabletsContaining Dextromethorphan Hydrobromide (DXM), Naproxen Sodium (NAP),and Docusate Sodium (DSS) at Benchtop Scale

Each hydrophilic matrix tablet lot was produced by dry-blending theactive substance(s) and excipients together followed by directcompression. The DXM and NAP (when present) were added together with allexcipients in an HDPE bag. Blending was accomplished by manually mixingthe contents of the bag for five minutes. Aliquots of the blend weremassed out using an analytical balance and were compressed using aManesty DC16 press. Each tablet aliquot was added to the die manually,and compressed at a speed of 5 rpm. Lots without NAP were compressedusing 0.3125-inch round, concave Natoli tooling (HOB No. 91300), whilelots containing NAP were compressed using 0.3750-inch round, concaveNatoli tooling (HOB No. 91380). The compression force was varied until atablet breaking force of 14-16 kPa was consistently achieved.

TABLE 1 Prototype formulation compositions (mg/tablet) Formulation(mg/tablet) Total Dextro- Granular Tablet methorphan Methocel AvicelNaproxen Docusate Mass Lot No. Hydrobromide K4M PH-302 Sodium Sodium(mg) Prototype 1-1 15.0 120.0 45.0 180.0 Prototype 1-2 15.0 120.0 45.017.6 197.6 Prototype 1-3 15.0 120.0 45.0 117.7 297.7 Prototype 1-4 15.0120.0 45.0 220.0 400.0 Prototype 1-5 15.0 120.0 45.0 220.0 8.8 408.8Prototype 1-6 15.0 120.0 45.0 220.0 17.6 417.6 Prototype 1-7 15.0 120.045.0 220.0 29.4 429.4 Prototype 1-8 15.0 120.0 45.0 220.0 117.7 517.7

USP Apparatus 2 was used for the dissolution testing of the prototypetablets produced. The dissolution samples were assayed for DXM usingHPLC with UV detection at 280 nm. The system parameters for both thechromatographic and dissolution analysis are shown below.

System: Hewlett Packard 1100 Series HPLC System

Column: Phenomenex Jupiter C18, 250×4.6 mm ID, 5μ, 300 Å

-   -   Part No.: 00G-4053-EO        Detector: UV detector, 280 nm        Mobile Phase A: 94.7/5.0/0.3 (v/v/v) water/methanol/TFA        Mobile Phase B: Pure methanol        Method Type Gradient        Flow Rate: 1.5 mL/min        Injection Volume: 30 μL        Run Time: 8.00 minutes (8.01-10.00 minutes is reequilibration)        Peakwidth: >0.1 min        Column Temperature: 35° C.        Autosampler temp: Ambient

TABLE 2 Gradient profile for HPLC mobile phases A and B Initial 60% A40% B 8.00 10% A 90% B 8.01 60% A 40% B 10.00  60% A 40% B

TABLE 3 Dissolution parameters Parameters Requirements Method Type USPApparatus 2 (Paddle Method) Rotation Speed 50 rpm Dissolution Media pH7.5 phosphate buffer (0.05M, potassium phosphate monobasic 0.68%/NaOH0.164%) Media Volume 900 mL Media Temperature 37.0 ± 0.5° C. SamplingTime Points 1, 2, 4, 6, 8, 10 and 12 hours 1, 2, 3, 6, 9, and 12 hoursSampling Volume 10 mL without media replacement (Use 10 μm Full-FlowFilter)

FIG. 1 illustrates zero-order release kinetics over 12 hours for DXMfrom the hydrophilic matrix containing naproxen sodium both with andwithout docusate sodium. Prototype 1-4 contains no DSS, indicating thatthe surfactant is not critical to achieving linear (i.e., zero-order)release kinetics. Prototypes 1-5 through 1-8 reveal that the addition ofsurfactant into the hydrophilic matrix does impact the rate and extentof release, with higher DSS levels showing a slower release rate and alower extent of release at 12 hours. Regardless of DSS level, alldissolution profiles in the presence of naproxen sodium are zero-order.

To further illustrate the importance of naproxen sodium and DSS to therelease kinetics of DXM from the hydrophilic matrix, FIG. 2 showsdissolution profiles for several formulations in which key componentshave been added or removed. Prototype 1-1 shows the release of DXM fromthe hydrophilic matrix in the absence of naproxen sodium and DSS. Thisformulation shows the largest extent of release; however, the releaseprofile is non-linear, indicating that zero-order release is notachieved. Prototypes 1-2 and 1-3 show the DXM release profile atincreasing levels of DSS (15 mg and 100 mg, respectively), revealingthat surfactant level can also be used to control the rate and extent ofDXM release when the NSAID salt is absent from the hydrophilic matrix.Prototypes 1-6 and 1-8 show DXM release profiles at the same two DSSconcentrations (15 mg and 100 mg, respectively) in the presence ofnaproxen sodium. Here, the addition of the NSAID salt to the matrixincreases the rate and extent of DXM release, while also causing therelease rate to become constant.

Example 2 Preparation of Sustained-release Hydrophilic Matrix TabletsContaining Dextromethorphan Hydrobromide (DXM), Naproxen, NaproxenSodium, Ibuprofen, Ibuprofen Sodium, and Docusate Sodium (DSS) atBenchtop Scale

Each hydrophilic matrix tablet lot was produced by dry-blending theactive substance(s) and excipients together followed by directcompression. The DXM and NSAID/NSAID salt were added together with allexcipients in an HDPE bag. Blending was accomplished by manually mixingthe contents of the bag for five minutes. Aliquots of the blend weremassed out using an analytical balance and were compressed using aManesty DC16 press. Each tablet aliquot was added to the die manuallyand compressed at a speed of 5 rpm. All lots were compressed using0.3750-inch round, concave Natoli tooling (HOB No. 91380). Thecompression force was varied until a tablet breaking force of 14-16 kPawas consistently achieved.

TABLE 4 Prototype formulation compositions (mg/tablet) Formulation(mg/tablet) Total Granular Tablet Lot Methocel Avicel Naproxen IbuprofenDocusate Mass No. DXM K4M PH-302 Sodium Naproxen Sodium Ibuprofen Sodium(mg) 2-1 15.0 120.0 45.0 220.0 17.6 417.6 2-2 15.0 120.0 45.0 220.0 17.6417.6 2-3 15.0 120.0 45.0 220.0 17.6 417.6 2-4 15.0 120.0 45.0 220.017.6 417.6

USP Apparatus 2 was used for the dissolution testing of the prototypetablets produced. The dissolution samples were assayed for DXM usingHPLC with UV detection at 280 nm. The system parameters for both thechromatographic and dissolution analysis are shown below.

System: Hewlett Packard 1100 Series HPLC System

Column: Phenomenex Jupiter C18, 250×4.6 mm ID, 5μ, 300 Å

-   -   Part No.: 00G-4053-EO        Detector: UV detector, 280 nm        Mobile Phase A: 94.7/5.0/0.3 (v/v/v) water/methanol/FA        Mobile Phase B: Pure methanol        Method Type Gradient        Flow Rate: 1.5 mL/min        Injection Volume: 30        Run Time: 8.00 minutes (8.01-10.00 minutes is reequilibration)        Peakwidth: >0.1 min        Column Temperature: 35° C.        Autosampler temp: Ambient

TABLE 5 Gradient profile for HPLC mobile phases A and B Initial 60% A40% B 8.00 10% A 90% B 8.01 60% A 40% B 10.00  60% A 40% B

TABLE 6 Dissolution parameters Parameters Requirements Method Type USPApparatus 2 (Paddle Method) Rotation Speed 50 rpm Dissolution Media pH7.5 phosphate buffer (0.05M, potassium phosphate monobasic 0.68%/NaOH0.164%) Media Volume 900 mL Media Temperature 37.0 ± 0.5° C. SamplingTime Points 1, 2, 4, 6, 8, 10 and 12 hours 1, 2, 3, 6, 9, and 12 hoursSampling Volume 10 mL without media replacement (Use 10 μm Full-FlowFilter)

FIG. 3 shows dissolution profiles for DXM from the hydrophilic matrix inpresence of NSAID and NSAID salts, demonstrating that zero-order releasekinetics depends on the presence of an NSAID salt faun (as opposed to aneutral free molecule). Prototypes 2-1 and 2-3 contain sodium salts ofnaproxen and ibuprofen, respectively. Prototypes 2-2 and 2-4 contain thefree base of naproxen and ibuprofen, respectively. All prototypescontain 15 mg of DSS. As shown in the figure, dissolution profiles forthe two prototypes containing the NSAID salt fauns are linear,indicating zero-order release for DXM from these formulations over 12hours. Conversely, the two prototypes containing the NSAID free baseforms show deviation from linearity, indicating that the release ratefor DXM from these formulations is not constant. (Note: Linear fits toeach curve have been included in the figure to guide the eye.)

Example 3 Preparation of Sustained-release Hydrophilic Matrix TabletsContaining Cyclobenzaprine Hydrochloride (CBP), Naproxen Sodium (NAP),and Docusate Sodium (DSS) at Benchtop Scale

Each hydrophilic matrix tablet lot was produced by dry-blending theactive substance(s) and excipients together followed by directcompression. The CBP and NAP (when present) were added together with allexcipients in an HDPE bag. Blending was accomplished by manually mixingthe contents of the bag for five minutes. Aliquots of the blend weremassed out using an analytical balance and were compressed using aManesty DC16 press. Each tablet aliquot was added to the die manuallyand compressed at a speed of 5 rpm. Lots without NAP were compressedusing 0.3125-inch round, concave Natoli tooling (HOB No. 91300), whilelots containing NAP were compressed using 0.3750-inch round, concaveNatoli tooling (HOB No. 91380). The compression force was varied until atablet breaking force of 14-16 kPa was consistently achieved.

TABLE 7 Prototype formulation compositions (mg/tablet) Formulation(mg/tablet) Total Granular Tablet Cyclobenzaprine Methocel AvicelNaproxen Docusate Mass Lot No. Hydrochloride K4M PH-302 Sodium Sodium(mg) Prototype 3-1 15.0 120.0 45.0 180.0 Prototype 3-2 15.0 120.0 45.017.6 197.6 Prototype 3-3 15.0 120.0 45.0 117.7 297.7 Prototype 3-4 15.0120.0 45.0 220.0 17.6 417.6 Prototype 3-5 15.0 120.0 45.0 220.0 117.7517.7

USP Apparatus 2 was used for the dissolution testing of the prototypetablets produced. The dissolution samples were assayed for CBP usingHPLC with UV detection at 280 nm. The system parameters for both thechromatographic and dissolution analysis are shown below.

System: Hewlett Packard 1100 Series HPLC System

Column: Phenomenex Jupiter C18, 250×4.6 mm ID, 5μ, 300 Å

-   -   Part No.: 00G-4053-EO        Detector: UV detector, 280 nm        Mobile Phase A: 94.7/5.0/0.3 (v/v/v) water/methanol/TFA        Mobile Phase B: Pure methanol        Method Type Gradient        Flow Rate: 1.5 mL/min        Injection Volume: 30 μL        Run Time: 8.00 minutes (8.01-10.00 minutes is reequilibration)        Peakwidth: >0.1 min        Column Temperature: 35° C.        Autosampler temp: Ambient

TABLE 8 Gradient profile for HPLC mobile phases A and B Initial 60% A40% B 8.00 10% A 90% B 8.01 60% A 40% B 10.00  60% A 40% B

TABLE 9 Dissolution parameters Parameters Requirements Method Type USPApparatus 2 (Paddle Method) Rotation Speed 50 rpm Dissolution Media pH7.5 phosphate buffer (0.05M, potassium phosphate monobasic 0.68%/NaOH0.164%) Media Volume 900 mL Media Temperature 37.0 ± 0.5° C. SamplingTime Points 1, 2, 4, 6, 8, 10 and 12 hours 1, 2, 3, 6, 9, and 12 hoursSampling Volume 10 mL without media replacement (Use 10 μm Full-FlowFilter)

To illustrate the importance of naproxen sodium and DSS to the releasekinetics of CBP from the hydrophilic matrix, FIG. 4 shows dissolutionprofiles for several formulations in which key components have beenadded or removed. Prototype 3-1 shows the release of CBP from thehydrophilic matrix in the absence of naproxen sodium and DSS. Thisformulation shows that the release profile is non-linear, indicatingthat zero-order release is not achieved. Prototypes 3-2 and 3-3 show theCBP release profile at increasing levels of DSS (15 mg and 100 mg,respectively), revealing that surfactant level can be used to controlthe rate and extent of CBP release when the NSAID salt is absent fromthe hydrophilic matrix. Prototypes 3-4 and 3-5 show CBP release profilesat the same two DSS concentrations (15 mg and 100 mg, respectively) inthe presence of naproxen sodium. Here, the addition of the NSAID salt tothe matrix increases the rate and extent of CBP release, while alsocausing the release rate to become constant (zero-order).

Example 4 Preparation of Sustained-release Hydrophilic Matrix TabletsContaining Benztropine Mesylate (BTP), Naproxen Sodium (NAP), andDocusate Sodium (DSS) at Benchtop Scale

Each hydrophilic matrix tablet lot was produced by dry-blending theactive substance(s) and excipients together followed by directcompression. The BTP and NAP (when present) were added together with allexcipients in an HDPE bag. Blending was accomplished by manually mixingthe contents of the bag for five minutes. Aliquots of the blend weremassed out using an analytical balance and were compressed using aManesty DC16 press. Each tablet aliquot was added to the die manuallyand compressed at a speed of 5 rpm. Lots without NAP were compressedusing 0.3125-inch round, concave Natoli tooling (HOB No. 91300), whilelots containing NAP were compressed using 0.3750-inch round, concaveNatoli tooling (HOB No. 91380). The compression force was varied until atablet breaking force of 14-16 kPa was consistently achieved.

TABLE 10 Prototype formulation compositions (mg/tablet) Formulation(mg/tablet) Benztropine Methocel Avicel Naproxen Granular Docusate TotalTablet Lot No. Mesylate K4M PH-302 Sodium Sodium Mass (mg) Prototype 4-115.0 120.0 45.0 180.0 Prototype 4-2 15.0 120.0 45.0 17.6 197.6 Prototype4-3 15.0 120.0 45.0 117.7 297.7 Prototype 4-4 15.0 120.0 45.0 220.0 17.6417.6 Prototype 4-5 15.0 120.0 45.0 220.0 117.7 517.7

USP Apparatus 2 was used for the dissolution testing of the prototypetablets produced. The dissolution samples were assayed for BTP usingHPLC with UV detection at 254 nm. The system parameters for both thechromatographic and dissolution analysis are shown below.

System: Hewlett Packard 1100 Series HPLC System

Column: Phenomenex Jupiter C18, 250×4.6 mm ID, 5μ, 300 Å

-   -   Part No.: 00G-4053-EO        Detector: UV detector, 254 nm        Mobile Phase A: 94.7/5.0/0.3 (v/v/v) water/methanol/TFA        Mobile Phase B: Pure methanol        Method Type Gradient        Flow Rate: 1.5 mL/min        Injection Volume: 30 μL        Run Time: 8.00 minutes (8.01-10.00 minutes is reequilibration)        Peakwidth: >0.1 min        Column Temperature: 35° C.        Autosampler temp: Ambient

TABLE 11 Gradient profile for HPLC mobile phases A and B Initial 60% A40% B 8.00 10% A 90% B 8.01 60% A 40% B 10.00  60% A 40% B

TABLE 12 Dissolution parameters Parameters Requirements Method Type USPApparatus 2 (Paddle Method) Rotation Speed 50 rpm Dissolution Media pH7.5 phosphate buffer (0.05M, potassium phosphate monobasic 0.68%/NaOH0.164%) Media Volume 900 mL Media Temperature 37.0 ± 0.5° C. SamplingTime Points 1, 2, 4, 6, 8, 10 and 12 hours 1, 2, 3, 6, 9, and 12 hoursSampling Volume 10 mL without media replacement (Use 10 μm Full-FlowFilter)

To illustrate the importance of naproxen sodium and DSS to the releasekinetics of BTP from the hydrophilic matrix, FIG. 5 shows dissolutionprofiles for several formulations in which key components have beenadded or removed. Prototype 4-1 shows the release of BTP from thehydrophilic matrix in the absence of naproxen sodium and DSS. Thisformulation shows that the release profile is non-linear, indicatingthat zero-order release is not achieved. Prototypes 4-2 and 4-3 show theBTP release profile at increasing levels of DSS (15 mg and 100 mg,respectively), revealing that surfactant level can be used to controlthe rate and extent of BTP release when the NSAID salt is absent fromthe hydrophilic matrix. Prototypes 4-4 and 4-5 show BTP release profilesat the same two DSS concentrations (15 mg and 100 mg, respectively) inthe presence of naproxen sodium. Here, the addition of the NSAID salt tothe matrix increases the rate and extent of BTP release, while alsocausing the release rate to become constant (zero-order).

Example 5 Preparation of Sustained-release Hydrophilic Matrix TabletsContaining Dextromethorphan Hydrobromide (DXM), Naproxen Sodium (NAP),and Sodium Lauryl Sulfate (SLS) at Benchtop Scale

Each hydrophilic matrix tablet lot was produced by dry-blending theactive substance(s) and excipients together followed by directcompression. The DXM and NAP (when present) were added together with allexcipients in an HDPE bag. Blending was accomplished by manually mixingthe contents of the bag for five minutes. Aliquots of the blend weremassed out using an analytical balance and were compressed using aManesty DC16 press. Each tablet aliquot was added to the die manuallyand compressed at a speed of 5 rpm. Lots without NAP were compressedusing 0.3125-inch round, concave Natoli tooling (HOB No. 91300), whilelots containing NAP were compressed using 0.3750-inch round, concaveNatoli tooling (HOB No. 91380). The compression force was varied until atarget tablet breaking force of 14−16 kPa was consistently achieved. Forseveral of the prototype formulations, the target tablet breaking forceof 15 kPa could not be achieved. In these cases, the compression forcewas increased until a maximum breaking force was realized: 8 kPa forPrototype 5-2, 9 kPa for Prototype 5-3, 14 kPa for Prototype 5-5, and 12kPa for prototype 5-6.

TABLE 13 Prototype formulation compositions (mg/tablet) Formulation(mg/tablet) Total Sodium Tablet Dextromethorphan Methocel AvicelNaproxen Lauryl Mass Lot No. Hydrobromide K4M PH-302 Sodium Sulfate (mg)Prototype 5-1 15.0 120.0 45.0 7.5 187.5 Prototype 5-2 15.0 120.0 45.015.0 195.0 Prototype 5-3 15.0 120.0 45.0 25.0 205.0 Prototype 5-4 15.0120.0 45.0 220.0 7.5 407.5 Prototype 5-5 15.0 120.0 45.0 220.0 15.0415.0 Prototype 5-6 15.0 120.0 45.0 220.0 25.0 425.0

USP Apparatus 2 was used for the dissolution testing of the prototypetablets produced. The dissolution samples were assayed for DXM usingHPLC with UV detection at 280 nm. The system parameters for both thechromatographic and dissolution analysis are shown below.

System: Agilent 1100 Series HPLC System

Column: Phenomenex Jupiter C18, 250×4.6 mm ID, 5μ, 300 Å

-   -   Part No.: 00G-4053-EO        Detector: UV detector, 280 nm        Mobile Phase A: 94.7/5.0/0.3 (v/v/v) water/methanol/TFA        Mobile Phase B: Pure methanol        Method Type Gradient        Flow Rate: 1.5 mL/min        Injection Volume: 30 μL        Run Time: 8.00 minutes (8.01-10.00 minutes is reequilibration)        Peakwidth: >0.1 min        Column Temperature: 35° C.        Autosampler temp: Ambient

TABLE 14 Gradient profile for HPLC mobile phases A and B Initial 60% A40% B 8.00 10% A 90% B 8.01 60% A 40% B 10.00  60% A 40% B

TABLE 15 Dissolution parameters Parameters Requirements Method Type USPApparatus 2 (Paddle Method) Rotation Speed 50 rpm Dissolution Media pH7.5 phosphate buffer (0.05M, potassium phosphate monobasic 0.68%/NaOH0.164%) Media Volume 900 mL Media Temperature 37.0 ± 0.5 C. SamplingTime Points 1, 3, 6, 9, and 12 hours Sampling Volume 10 mL without mediareplacement (Use 10 μm Full-Flow Filter)

FIG. 6 illustrates first-order release kinetics over 12 hours for DXMformulations that contain varying levels of SLS (7.5 mg-25 mg) withoutthe addition of naproxen sodium. The results are similar to those seenfor comparable prototypes that contain DXM, DSS and no naproxen sodium(FIG. 2). The surfactant (DSS or SLS) strongly retards the release ofDXM. Close inspection of the data reveals first-order release, even forthe slower releasing formulations.

Addition of naproxen sodium to the formulations containing SLS resultsin zero-order drug release profiles (FIG. 7). Again, this is similar torelease profiles seen for formulations containing DSS. Comparison tomatrix tablets of similar composition (FIG. 6) shows that the additionof naproxen sodium increases the rate and linearizes the releaseprofiles. For tablets containing DXM, SLS and naproxen sodium, releaseprofiles are very similar for increasing levels of SLS with the highestSLS level releasing slightly faster than the other two. It should benoted that other formulation parameters (for example grade of HPMC)could be used to further tailor release profiles for formulationscontaining surfactant.

Example 6 Preparation of Sustained-release Hydrophilic Matrix TabletsContaining Dextromethorphan Hydrobromide (DXM), Docusate Sodium (DSS)and Varying Levels of Naproxen Sodium (NAP) at Benchtop Scale

Each hydrophilic matrix tablet lot was produced by dry-blending theactive substance(s) and excipients together followed by directcompression. The DXM and NAP were added together with all excipients inan HDPE bag. Blending was accomplished by manually mixing the contentsof the bag for five minutes. Aliquots of the blend were massed out usingan analytical balance and were compressed using a Manesty DC16 press.Each tablet aliquot was added to the die manually and compressed at aspeed of 5 rpm. Prototypes 6-1, 6-2 and 6-3 were compressed using0.3125-inch round, concave Natoli tooling (HOB No. 91300), whileprototype 6-4 was compressed using 0.3750-inch round, concave Natolitooling (HOB No. 91380). The compression force was varied until a tabletbreaking force of 14−16 kPa was consistently achieved.

TABLE 16 Prototype formulation compositions (mg/tablet) Formulation(mg/tablet) Total Granular Tablet Dextromethorphan Methocel AvicelNaproxen Docusate Mass Lot No. Hydrobromide K4M PH-302 Sodium Sodium(mg) Prototype 6-1 15.0 120.0 45.0 27.5 17.6 225.1 Prototype 6-2 15.0120.0 45.0 55.0 17.6 252.6 Prototype 6-3 15.0 120.0 45.0 110.0 17.6307.6 Prototype 6-4 15.0 120.0 45.0 220.0 17.6 417.6

USP Apparatus 2 was used for the dissolution testing of the prototypetablets produced. The dissolution samples were assayed for DXM usingHPLC with UV detection at 280 nm. The system parameters for both thechromatographic and dissolution analysis are shown below.

System: Agilent 1100 Series HPLC System

Column: Phenomenex Jupiter C18, 250×4.6 mm ID, 5μ, 300 Å

-   -   Part No.: 00G-4053-EO        Detector: UV detector, 280 nm        Mobile Phase A: 94.7/5.0/0.3 (v/v/v) water/methanol/TFA        Mobile Phase B: Pure methanol        Method Type Gradient        Flow Rate: 1.5 mL/min        Injection Volume: 30 μL,        Run Time: 8.00 minutes (8.01-10.00 minutes is reequilibration)        Peakwidth: >0.1 min        Column Temperature: 35° C.        Autosampler temp: Ambient

TABLE 17 Gradient profile for HPLC mobile phases A and B Initial 60% A40% B 8.00 10% A 90% B 8.01 60% A 40% B 10.00  60% A 40% B

TABLE 18 Dissolution parameters Parameters Requirements Method Type USPApparatus 2 (Paddle Method) Rotation Speed 50 rpm Dissolution Media pH7.5 phosphate buffer (0.05M, potassium phosphate monobasic 0.68%/NaOH0.164%) Media Volume 900 mL Media Temperature 37.0 ± 0.5 C. SamplingTime Points 1, 3, 6, 9 and 12 hours Sampling Volume 10 mL without mediareplacement (Use 10 μm Full-Flow Filter)

The impact of NSAID level on release profiles is shown in FIG. 8 forformulations having constant DXM and DSS with varying amounts ofnaproxen sodium. Zero-order release profiles are realized for naproxensodium levels of 220 and 110 mg; however, slight deviation fromzero-order can be seen for lower levels of naproxen sodium (55 and 27.5mg), suggesting that there is a minimum threshold for naproxen sodiumlevel needed to achieve constant release kinetics in the currentformulation. Increasing naproxen sodium clearly has a significant impacton the rate of release, with the rate of DXM increasing with increasingNAP level.

Example 7 Evaluation of “Dose Dumping” and Drug Extraction for PrototypeFormulations Containing Dextromethorphan Hydrobromide (DXM), NaproxenSodium (NAP) and Docusate Sodium (DSS)

Each hydrophilic matrix tablet lot was produced by dry-blending theactive substance(s) and excipients together followed by directcompression. The DXM and NAP were added together with all excipients inan HDPE bag. Blending was accomplished by manually mixing the contentsof the bag for five minutes. Aliquots of the blend were massed out usingan analytical balance and were compressed using a Manesty DC16 press.Each tablet aliquot was added to the die manually and compressed at aspeed of 5 rpm. Prototypes 7-1, 7-2 and 7-3 were compressed using0.3750-inch round, concave Natoli tooling (HOB No. 91380). Thecompression force was varied until a tablet breaking force of 14-16 kPawas consistently achieved.

TABLE 19 Prototype formulation compositions (mg/tablet) Formulation(mg/tablet) Total Granular Tablet Dextromethorphan Methocel AvicelNaproxen Docusate Mass Lot No. Hydrobromide K4M PH-302 Sodium Sodium(mg) Prototype 7-1 15.0 120.0 45.0 220.0 17.6 417.6 Prototype 7-2 15.0120.0 45.0 220.0 29.4 429.4 Prototype 7-3 15.0 120.0 45.0 220.0 58.8458.8Dose-Dumping

The hydroalcoholic “dose dumping” experiment investigates the in vitrodrug release behavior in the presence of alcohol. The experiment modelsingestion of a tablet with the concomitant use of alcoholic beverages(i.e., ethanol). In order to assess the potential for “dose dumping,”the dissolution method was modified by changing the media to 0.1N HClwith varying levels of alcohol (ethanol). USP Apparatus 2 was used forthe dissolution testing of the prototype tablets produced. Thedissolution samples were assayed for DXM using HPLC with UV detection at280 nm. The system parameters for both the chromatographic anddissolution analysis are shown below.

System: Agilent 1100 series HPLC system

Column: Phenomenex Jupiter C18, 250×4.6 mm ID, 5μ, 300 Å

-   -   Part No.: 00G-4053-EO        Detector: UV detector, 280 nm        Mobile Phase A: 94.7/5.0/0.3 (v/v/v) water/methanol/TFA        Mobile Phase B: Pure methanol        Method Type: Gradient        Flow Rate: 1.5 mL/min        Injection Volume: 30 μL        Run Time: 8.00 minutes (8.01-10.00 minutes is reequilibration)        Peakwidth: >0.1 min        Column Temperature: 35° C.        Autosampler temp: Ambient

TABLE 20 Gradient profile for HPLC mobile phases A and B Initial 60% A40% B 8.00 10% A 90% B 8.01 60% A 40% B 10.00  60% A 40% B

TABLE 21 Dissolution parameters Parameters Requirements Method Type USPApparatus 2 (Paddle Method) Rotation Speed 50 rpm Dissolution Media pH1.2 USP buffer pH 1.2 USP buffer (5% ethanol) pH 1.2 USP buffer (20%ethanol) Media Volume 900 mL Media Temperature 37.0 ± 0.5 C. SamplingTime Points 1, 3, 6, 9 and 12 hours Sampling Volume 8 mL without mediareplacement (Use 10 μm Full-Flow Filter)

The purpose of this investigation was to measure the integrity of thedosage formulation using acidic, hydroalcoholic dissolution media. Forthis experiment, intact tablets were evaluated. Prototype 7-1 wasevaluated since this formulation is expected to show significantlygreater DXM release over 12 hours compared to Prototypes 7-2 and 7-3based on evaluation of previous formulations of similar composition.

The experimental design was to simulate simultaneous oral ingestion ofalcohol and the matrix tablet. Dissolution profiles are provided in FIG.9. The results demonstrate that “dose dumping” does not occur, even witha 20% ethanol level in the dissolution media. In addition, zero-orderrelease is maintained from 0-20% ethanol.

Drug Extraction

The small-volume extraction experiment models the attempted extractionof drug that a substance abuser might undertake. In this experiment,tablets were crushed and extracted with two common solvents, water and40% alcohol. A single tablet was crushed and stirred with a small volumeof solvent (50 mL). At time points of 30 minutes and 12 hours, aliquotswere removed and assayed for both DXM and docusate. Prior to HPLCanalysis the aliquots were filtered using a 10 μm full-flow filter andsubsequently centrifuged at 1000 rpm for 30 minutes. The supernatantfrom this procedure was filled directly into HPLC vials for analysis.The HPLC assay for DXM has been described previously. The following HPLCmethod was developed to assay docusate:

System: Agilent 1100 series HPLC system

Column: YMC-Pack CN, 250 mm×4.6 mm ID, 5 μm, 120 Å

-   -   Part number: CN12S052546WT        Detector: UV detector, 225 nm        Mobile Phase A: 0.02M tetrabutylammonium hydrogen sulfate        Mobile Phase B: Pure acetonitrile        Method Type: Isocratic 40% A/60% B        Flow Rate: 1.5 mL/min        Injection Volume: 10 μL        Run Time: 5 minutes        Peakwidth: >0.1 min        Column Temperature: 45° C.        Autosampler temp: Ambient

TABLE 22 Simultaneous Release of Dextromethorphan Hydrobromide andDocusate Sodium From Crushed Tablets to Assess Abuse Potential DXMDocusate DXM Docusate Released Released Released Released Extraction in30 in 30 in in Formulation Solvent minutes minutes 12 hours 12 hoursPrototype 1 Water 58% 80% 47% 61% Prototype 1 Alcohol 93% 91% 100% 98%40% Prototype 2 Water 35% 47% 35% 47% Prototype 2 Alcohol 95% 93% 114%108% 40% Prototype 3 Water 52% 48% 50% 43% Prototype 3 Alcohol 68% 67%102% 95% 40%

The data (Table 22) demonstrates the simultaneous release of DXM anddocusate from formulations containing different levels of docusate(Table 19). This data shows that extraction and separation of DXM anddocusate from these formulations would require advanced chemicalknowledge and substantial effort, and would likely be time-consuming.The commingling of DXM (or other active) and docusate would makeinjection of extracted solutions unattractive to an abuser andpotentially harmful. Additionally, drying the solution to create a solidwould be of no benefit to a drug abuser, as the solid would be impureand contain irritating docusate.

Example 8 Preparation of Sustained Release Hydrophilic Matrix TabletsContaining Amantadine Hydrochloride, Docusate Sodium (DSS) and NaproxenSodium (NAP) at Benchtop Scale

Each hydrophilic matrix tablet lot was produced by dry-blending theactive substance(s) and excipients together followed by directcompression. The Amantadine HCl and NAP were added together with allexcipients in an HDPE bag. Blending was accomplished by manually mixingthe contents of the bag for five minutes. Aliquots of the blend weremassed out using an analytical balance and were compressed using aManesty DC16 press. Each tablet aliquot was added to the die manuallyand compressed at a speed of 10 rpm. Prototype 8-1 was compressed using0.375 inch round, concave Natoli tooling (HOB No. 91380). Prototypes 8-2and 8-3 were compressed using 0.3125 inch round, concave Natoli tooling(HOB #91300). The compression force was varied until a tablet breakingforce of 14-16 kp was consistently achieved.

TABLE 23 Prototype formulation compositions (mg/tablet) Formulation(mg/tablet) Amantadine Methocel Avicel Naproxen Granular Docusate TotalTablet Lot No. Hydrochloride K4M PH-302 Sodium Sodium Mass (mg)Prototype 8-1 15.0 120.1 45.0 219.8 17.1 417.0 Prototype 8-2 15.0 120.145.0 0.0 17.1 197.2 Prototype 8-3 15.0 120.1 45.0 0.0 0.0 180.1

Amantadine hydrochloride is a freely soluble drug that lacks achromophore. Direct injection GC (gas chromatography) with a memantineinternal standard allows for rapid and accurate analysis of dissolutionsamples. Baseline resolution between the amantadine and memantineinternal standard ensures the integrity of the GC procedure.

Dissolution testing of matrix tablets was performed using USP Apparatus2. At each specified time point, approximately 8 ml of media was removedusing a stainless steel cannula. Samples were filtered using porous(full-flow) filters (QLA, Inc., Bridgewater, N.J., part numberFIL035-01). A memantine internal standard was prepared by dissolving aknown quantity of memantine standard in methanol and diluting (usingvolumetric glassware) to achieve a final concentration of ≈0.02 mg/ml.Each dissolution sample was diluted with an equal volume of memantineinternal standard solution to result in a memantine internal standardconcentration of ≈0.01 mg/ml. A chromatographic standard was preparedwith the final concentration of amantadine at ≈0.01 mg/ml and memantineat ≈0.01 mg/ml. The final composition of samples and standards was50%/50% (methanol/aqueous) on a volume/volume basis using thisprocedure. Every six samples were bracketed by chromatographicstandards. Calculations were done using peak area ratios (amantadinearea/memantine internal standard area). Drug released at each time pointincludes corrections for changes in vessel volume and the amount of drugremoved during previous sample pulls. Media replacement was notperformed. The system parameters for both the chromatographic anddissolution analysis are shown below.

TABLE 24 Dissolution parameters Parameters Requirements Method Type USPApparatus 2 (Paddle Method) Rotation Speed 50 rpm Dissolution Media pH7.5 phosphate buffer (0.05M, potassium phosphate monobasic 0.68%/NaOH0.164%) Media Volume 900 mL Media Temperature 37.0 ± 0.5 C. SamplingTime Points 1, 3, 6, 9, 12, 18 and 24 hours Sampling Volume 8 mL withoutmedia replacement (Use 35 μm Full-Flow Filter)

TABLE 25 GC parameters Parameters Requirements Method Type GasChromatography (HP 5890 Series II) GC Column Zebron ZB-5, 30 m × 0.53mm, 5 μm film thickness, Phenomenex cat # 7HK-G002-39 Injection Volume1.0 μl Injection Mode Direct injection Injector Liner Cyclo-UnilinerLiner, Siltek Deactivated, 4 × 6.3 × 78.5 mm, Restek cat.# 20338-214.5Injector Temperature 220° C. Detector Temperature 250° C. Carrier GasHelium at 3.0 psi Detector Flame ionization detector Detector GasHydrogen/air mixture Gradient program Initial temperature: 140°, holdfor 15 minutes, ramp at 20° C./min for 5 minutes, final temp 240° C.,hold for 1 minute at 240°

The results for the amantadine hydrochloride matrix tablet containingnaproxen sodium and DSS (Prototype 8-1) shows zero-order release. Thisdemonstrates the applicability of the invention to drugs containing theprimary amine functional group. The formulation that does not containnaproxen sodium and DSS (prototype 8-3) exhibits first-order release.Formulation 8-2 contains DSS (with no naproxen sodium) and shows aslower release compared to 8-3, providing addition evidence thatdocusate retards drug release without achieving a zero-order releaseprofile. Note that the formulation containing amantadine hydrochloride,naproxen sodium and DSS (Prototype 8-1) exhibits sustained, zero-orderrelease out to 24 hours, demonstrating the utility of the invention forq.d. as well as b.i.d, dosing.

Example 9 Preparation of Sustained Release Hydrophilic Matrix TabletsContaining Memantine Hydrochloride, Docusate Sodium (DSS) and NaproxenSodium (NAP) at Benchtop Scale

Each hydrophilic matrix tablet lot was produced by dry-blending theactive substance(s) and excipients together followed by directcompression. The Memantine HCl and NAP were added together with allexcipients in a 100 cc glass jar. Blending was accomplished using aGlobePharma Miniblend Table-Top Blender (10 min. @ 28 rpm). Aliquots ofthe blend were massed out using an analytical balance and werecompressed using a Manesty DC16 press. Each tablet aliquot was added tothe die manually and compressed at a speed of 3 rpm. Prototype 9-1 wascompressed using 0.3750 in. round, concave Natoli tooling (HOB #91380)while prototypes 9-2 and 9-3 were compressed using 0.3125 in. round,concave Natoli tooling (HOB #91300). The compression force was varieduntil a tablet breaking force of 14-16 kp was consistently achieved.

TABLE 26 Prototype formulation compositions (mg/tablet) Formulation(mg/tablet) Memantine Methocel Avicel Naproxen Granular Docusate TotalTablet Lot No. Hydrochloride K4M PH-302 Sodium Sodium Mass (mg)Prototype 9-1 15.0 120.1 45.0 219.8 17.1 417.0 Prototype 9-2 15.0 120.145.0 0.0 17.1 197.2 Prototype 9-3 15.0 120.1 45.0 0.0 0.0 180.1

Memantine hydrochloride is structurally similar to amantadine and lacksa chromophore. Though less soluble than amantadine hydrochloride,memantine hydrochloride is soluble in water. Direct injection GC (gaschromatography) with an amantadine internal standard allows for rapidand accurate analysis of dissolution samples. Baseline resolutionbetween the memantine and the amantadine internal standard ensures theintegrity of the GC procedure.

Dissolution testing of matrix tablets was performed using USP Apparatus2. At each specified time point, approximately 8 ml of media was removedusing a stainless steel cannula. Samples were filtered using porous(full-flow) filters (QLA, Inc., Bridgewater, N.J., part numberFIL035-01). The amantadine internal standard was prepared by dissolvinga known quantity of amantadine standard in methanol and diluting (usingvolumetric glassware) to achieve a final concentration of 0.02 mg/ml.Each dissolution sample was diluted with an equal volume of amantadineinternal standard solution to result in an amantadine internal standardconcentration of 0.01 mg/ml. A chromatographic standard was preparedwith the final concentration of memantine at ≈0.01 mg/ml and amantadineat ≈0.01 mg/ml. The final composition of samples and standards was50%/50% (methanol/aqueous) on a volume/volume basis using thisprocedure. Every six samples were bracketed by chromatographicstandards. Calculations were done using peak area ratios (memantinearea/amantadine internal standard area). Drug released at each timepoint includes corrections for changes in vessel volume and the amountof drug removed during previous sample pulls. Dissolution mediareplacement was not performed. The system parameters for both thechromatographic and dissolution analysis are shown below.

TABLE 27 Dissolution parameters Parameters Requirements Method Type USPApparatus 2 (Paddle Method) Rotation Speed 50 rpm Dissolution Media pH7.5 phosphate buffer (0.05M, potassium phosphate monobasic 0.68%/NaOH0.164%) Media Volume 900 mL Media Temperature 37.0 ± 0.5 C. SamplingTime Points 1, 3, 6, 9, 12, 18 and 24 hours Sampling Volume 8 mL withoutmedia replacement (Use 35 μm Full-Flow Filter)

TABLE 28 GC parameters Parameters Requirements Method Type GasChromatography (HP 5890 Series II) GC Column Zebron ZB-5, 30 m × 0.53mm, 5 μm film thickness, Phenomenex cat # 7HK-G002-39 Injection Volume1.0 μl Injection Mode Direct injection Injector Liner Cyclo-UnilinerLiner, Siltek Deactivated, 4 × 6.3 × 78.5 mm, Restek cat.# 20338-214.5Injector Temperature 220° C. Detector Temperature 250° C. Carrier GasHelium at 3.0 psi Detector Flame ionization detector Detector GasHydrogen/air mixture Gradient program Initial temperature: 140°, holdfor 15 minutes, ramp at 20° C./min for 5 minutes, final temp 240° C.,hold for 1 minute at 240°

The results for memantine hydrochloride provide additional evidence ofthe suitability of the matrix tablet technology for drugs containing theprimary amine group. For example, Prototype 9-3 is a standard HPMCmatrix tablet that shows first-order release of memantine. Thisformulation does not contain naproxen sodium or DSS. Prototype 9-2 is acomparable formulation with the addition of DSS. Retardation of drugrelease is seen in this case with the preservation of the first-orderprofile. Prototype 9-1 is a prototype containing memantinehydrochloride, naproxen sodium and DSS. The desirable zero-order releaseprofile is achieved by the combination of components in thisformulation.

Example 10 Preparation of Sustained Release Hydrophilic Matrix TabletsContaining Ritodrine Hydrochloride, Docusate Sodium (DSS) and NaproxenSodium (NAP) at Benchtop Scale

Each hydrophilic matrix tablet lot was produced by dry-blending theactive substance(s) and excipients together followed by directcompression. The ritodrine hydrochloride and naproxen sodium were addedtogether with all excipients in a 100 cc glass jar. Blending wasaccomplished using a GlobePharma Miniblend Table-Top Blender (10 min. @28 rpm). Aliquots of the blend were massed out using an analyticalbalance and were compressed using a Manesty DC16 press. Each tabletaliquot was added to the die manually and compressed at a speed of 3rpm. Prototype 10-1 was compressed using 0.3750 in. round, concaveNatoli tooling (HOB #91380) while prototypes 10-2 and 10-3 werecompressed using 0.3125 in. round, concave Natoli tooling (HOB #91300).The compression force was varied until a tablet breaking force of 14-16kp was consistently achieved.

TABLE 29 Prototype Formulation compositions (mg/tablet) Formulation(mg/tablet) Ritodrine Methocel Avicel Naproxen Granular Docusate TotalTablet Lot No. Hydrochloride K4M PH-302 Sodium Sodium Mass (mg)Prototype 10-1 15.0 120.1 45.0 219.8 17.1 417.0 Prototype 10-2 15.0120.1 45.0 0.0 17.1 197.2 Prototype 10-3 15.0 120.1 45.0 0.0 0.0 180.1

Ritodrine hydrochloride is taken orally as a tocolytic agent. The drugcontains a secondary amine group and absorbs light in the UV region.Matrix tablets containing ritodrine were manufactured and evaluated withthe goal of determining the applicability of the present invention todrugs containing the secondary amine functional group. The analysis ofdissolution samples is done using HPLC with UV detection. Externalchromatographic standards were used to quantify the amount of ritodrinereleased.

Dissolution testing of matrix tablets was performed using USP Apparatus2. At each specified time point, approximately 8 ml of media was removedusing a stainless steel cannula. Samples were filtered using porous(full-flow) filters (QLA, Inc., Bridgewater, N.J., part numberFIL035-01). A chromatographic standard was prepared with the finalconcentration of Ritodrine at ≈0.02 mg/ml. The diluent for preparing thechromatographic standards was dissolution media/acetonitrile in a90%/10% volume/volume ratio. For each dissolution sample 1.0 ml wasquantitatively transferred into an HPLC vial. An amount of acetonitrile(110 μl) was added to each HPLC vial to ensure a constant solventcomposition between samples and standards. Every six samples werebracketed by chromatographic standards. Calculations were done bycomparing the sample ritodrine peak area to the mean ritodrine peak areaof the chromatographic standards. Drug released at each time pointincludes corrections for changes in vessel volume and the amount of drugremoved during previous sample pulls. Dissolution media replacement wasnot performed. The system parameters for both the chromatographic anddissolution analysis are shown below.

TABLE 30 Dissolution parameters Parameters Requirements Method Type USPApparatus 2 (Paddle Method) Rotation Speed 50 rpm Dissolution Media pH7.5 phosphate buffer (0.05M, potassium phosphate monobasic 0.68%/NaOH0.164%) Media Volume 900 mL Media Temperature 37.0 ± 0.5 C. SamplingTime Points 1, 3, 6, 9, 12, 18 and 24 hours Sampling Volume 8 mL withoutmedia replacement (Use 35 μm Full-Flow Filter)

TABLE 31 HPLC Parameters System: Agilent 1100 series HPLC system Column:Hypersil Gold (Thermo Scientific) C18, 250 × 4.6 mm ID, 5μ, 175 Å (PartNo.: 25005-254630) Detector: UV detector, 270 nm Mobile Phase A: 75/25(% v/% v) buffer/acetonitrile Buffer: 0.02M KH₂PO₄ (adjust to final pHof 4.0 with H₃PO₄) Method Type: Isocratic Flow Rate: 1.0 mL/minInjection Volume: 15 μL Run Time 10.00 minutes Peakwidth: >0.1 minColumn Temperature: 35° C. Autosampler temp: Ambient

The results show the validity of the matrix tablet technology for drugscontaining the secondary amine functional group. Prototype 10-3 showsthe first-order release that is typical for hydrophilic matrix tabletsystems. Consistent with the other Examples, the addition of docusateretards release (Prototype 10-2). Prototype 10-1 contains a combinationof components (ritodrine, naproxen sodium, and docusate) that permitszero-order release to be obtained.

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. Variousmodifications and alterations to this invention will become apparent tothose skilled in the art without departing from the scope and spirit ofthis invention. It should be understood that this invention is notintended to be unduly limited by the illustrative embodiments andexamples set forth herein and that such examples and embodiments arepresented by way of example only with the scope of the inventionintended to be limited only by the claims set forth herein.

What is claimed is:
 1. A sustained-release oral pharmaceutical composition comprising within a single dosage form: a hydrophilic matrix; a therapeutically effective amount of a non-opioid amine-containing compound; and a salt of a non-steroidal anti-inflammatory drug (NSAID); wherein the non-opioid amine-containing compound and the salt of an NSAID are within the hydrophilic matrix; and wherein the composition exhibits a release profile with respect to the non-opioid amine-containing compound, wherein the release profile comprises a substantial portion that is representative of zero-order release kinetics under in vitro conditions as a result of dissolution of the hydrophilic matrix.
 2. A sustained-release oral pharmaceutical composition comprising within a single dosage form: a hydrophilic matrix; a therapeutically effective amount of a non-opioid amine-containing compound; a salt of a non-steroidal anti-inflammatory drug (NSAID); and a pharmaceutically acceptable anionic surfactant; wherein the non-opioid amine-containing compound, the salt of an NSAID, and the anionic surfactant are within the hydrophilic matrix; and wherein the composition exhibits a release profile with respect to the non-opioid amine-containing compound, wherein the release profile comprises a substantial portion that is representative of zero-order release kinetics under in vitro conditions as a result of dissolution of the hydrophilic matrix.
 3. The composition of claim 1 wherein the non-opioid amine-containing compound comprises an amine group, and wherein the amine group comprises a secondary amine, a tertiary amine, a primary amine, or combination thereof.
 4. The composition of claim 1 wherein the non-opioid amine-containing compound comprises a tertiary amine.
 5. The composition of claim 2 wherein the non-opioid amine-containing compound is selected from the group consisting of dextromethorphan, cyclobenzaprine, benztropine, baclofen, arbaclofen, ritodrine, tizanidine, flurazepam, chlorpheniramine, doxylamine, diphenhydramine, diltiazem, rimantadine, amantadine, memantine, and combinations thereof.
 6. The composition of claim 1 wherein the non-opioid amine-containing compound is a salt comprising a hydrochloride, a bitartrate, an acetate, a naphthylate, a tosylate, a mesylate, a besylate, a succinate, a palmitate, a stearate, an oleate, a pamoate, a laurate, a valerate, a hydrobromide, a sulfate, a methane sulfonate, a tartrate, a citrate, a maleate, or a combination of the foregoing.
 7. The composition of claim 1 wherein the NSAID salt is selected from the group consisting of a salicylate derivative, a 2-aryl propionic acid derivative, a pyrazolidine derivative, an N-arylanthranilic acid derivative, an oxicam derivative, an arylalkanoic acid, an indole derivative, and combinations thereof.
 8. The composition of claim 2, wherein the pharmaceutically acceptable anionic surfactant is selected from the group consisting of monovalent alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acyl glutamates, fatty acid-polypeptide condensates, sulfur-containing surfactants, phosphated ethoxylated alcohols, and combinations thereof.
 9. The composition of claim 1 wherein the NSAID salt is present in an amount effective to provide zero-order release kinetics under in vitro conditions.
 10. The composition of claim 2 wherein the pharmaceutically acceptable anionic surfactant is present in a release-modifying amount.
 11. The composition of claim 1 wherein the single dosage form is a tablet form.
 12. The composition of claim 1 wherein the hydrophilic matrix comprises at least one hydrophilic polymeric compound selected from the group consisting of a gum, a cellulose ether, an acrylic resin, a polyvinyl pyrrolidone, a protein-derived compound, and combinations thereof.
 13. A sustained-release oral pharmaceutical composition comprising within a single dosage form: a hydrophilic matrix; a therapeutically effective amount of an amine-containing compound selected from the group consisting of dextromethorphan, cyclobenzaprine, benztropine, ritodrine, memantine, amantadine, salts thereof, and combinations thereof; and a salt of a non-steroidal anti-inflammatory drug (NSAID) selected from the group consisting of a salt of naproxen, diclofenac, ibuprofen, and combinations thereof; wherein the amine-containing compound and the salt of an NSAID are within the hydrophilic matrix; and wherein the composition exhibits a release profile of the amine-containing compound, wherein the release profile comprises a substantial portion that is representative of zero-order release kinetics under in vitro conditions.
 14. A sustained-release oral pharmaceutical composition comprising within a single dosage form: a hydrophilic matrix; a therapeutically effective amount of an amine-containing compound selected from the group consisting of dextromethorphan, cyclobenzaprine, benztropine, ritodrine, memantine, amantadine, salts thereof, and combinations thereof; a salt of a non-steroidal anti-inflammatory drug (NSAID) selected from the group consisting of a salt of naproxen, diclofenac, ibuprofen, and combinations thereof; and a pharmaceutically acceptable anionic surfactant selected from the group consisting of sodium lauryl sulfate, docusate sodium, docusate calcium, and combinations thereof; wherein the amine-containing compound, the salt of an NSAID, and the anionic surfactant are within the hydrophilic matrix; and wherein the composition exhibits a release profile of the amine-containing compound, wherein the release profile comprises a substantial portion that is representative of zero-order release kinetics under in vitro conditions.
 15. A method of providing a desired effect in a subject, the method comprising administering to a subject a composition of claim 1, wherein the desired effect is pain treatment, cough suppression, muscle relaxation, treatment of migraine headaches, treatment of spasms, treatment of convulsions, antihistamine effect, anti-inflammatory effect, antihypertensive effect, antiviral effect, treatment of Parkinson's Disease, or treatment of Alzheimer's Disease.
 16. The method of claim 15 wherein administering the composition comprises administering once or twice per day.
 17. The method of claim 16 wherein administering the composition comprises administering once per day. 